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The Expanding Role of Immunotherapy
Abstract
The use of agents able to modulate the immune system to induce or potentiate its anti-tumour activity is not a new strategy in oncology. However, the development of new agents such as immune checkpoint inhibitors has achieved unprecedented efficacy results in a wide variety of tumours, dramatically changing the landscape of cancer treatment in recent years. Ipilimumab, nivolumab, pembrolizumab or atezolizumab are now standard of care options in several malignancies and new indications are being approved on a regular basis in different tumours. Moreover, there are many other novel immunotherapy strategies that are currently being assessed in clinical trials. Agonists of co-stimulatory signals, adoptive cell therapies, vaccines, virotherapy and others have raised interest as therapeutic options against cancer. In addition, many of these novel approaches are being developed both in monotherapy and as part of combinatory regimes in order to synergize their activity. The results from those studies will help to define the expanding role of immunotherapy in cancer treatment in a forthcoming future.
... An efficient cancer vaccine should ideally be able to reinforce the body's natural defenses against cancer by eliciting potent CD4+ and CD8+ T effector and memory response [12]. Cancer vaccines come in a variety of forms which include cell-based vaccines/whole tumor cells [33,34], viral/bacterial-based vaccines [34][35][36], gene-based vaccines [13,34,37], and protein/peptide vaccines [34,38]. ...
... HPV is a double-stranded, circular DNA [124] and the most prevalent sexually transmitted virus. High-risk HPV types (HPV16, 18,31,33,35,39,45,51,52,56,58,59) are the leading causes of genital tract cancers, including cervical, vulvar, vaginal, penile, and anal cancers, and a subset of head and neck cancers [125]. Subtypes 16, 18, and 33 are associated with 29% of breast cancer. ...
Breast and gynecologic cancers are significant global threats to women’s health and those living with the disease require lifelong physical, financial, and social support from their families, healthcare providers, and society as a whole. Cancer vaccines offer a promising means of inducing long-lasting immune response against the disease. Among various types of cancer vaccines available, peptide vaccines offer an effective strategy to elicit specific anti-tumor immune responses.
Peptide vaccines have been developed based on tumor associated antigens (TAAs) and tumor specific neoantigens which can also be of viral origin. Molecular alterations in HER2 and non-HER2 genes are established to be involved in the pathogenesis of female-specific cancers and hence were exploited for the development of peptide vaccines against these diseases, most of which are in the latter stages of clinical trials. However, prophylactic vaccines for viral induced cancers, especially those against Human Papillomavirus (HPV) infection are well established. This review discusses therapeutic and prophylactic approaches for various types of female-specific cancers such as breast cancer and gynecologic cancers with special emphasis on peptide vaccines. We also present a pipeline for the design and evaluation of a multiepitope peptide vaccine that can be active against female-specific cancers.
... The immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1) have been the first kind of drugs that gave patients hope and revolutionized the treatment of cancers previously thought to be incurable [1]. Since the establishment of immunotherapy approaches, dozens of immune checkpoint inhibitors were studied for the treatment of different cancers with various degrees of success [2,3]. The breakthroughs of immunotherapy had an avalanche effect and stimulated the research of multiple combinatorial approaches for cancer treatment [4,5]. ...
... Reassuring results indicate that the combination of talimogene laherparepvec with ipilimumab has greater efficacy than either therapy alone, without additional safety concerns above those expected for both medicines in monotherapy. Thus, 38 patients with melanoma (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response, and importantly, responses were not limited to injected lesions: responses in the visceral lesion were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm [3]. ...
Recent cancer immunotherapy breakthroughs have fundamentally changed oncology and revived the fading hope for a cancer cure. The immune checkpoint inhibitors (ICI) became an indispensable tool for the treatment of many malignant tumors. Alongside ICI, the application of oncolytic viruses in clinical trials is demonstrating encouraging outcomes. Dozens of combinations of oncolytic viruses with conventional radiotherapy and chemotherapy are widely used or studied, but it seems quite complicated to highlight the most effective combinations. Our review summarizes the results of clinical trials evaluating oncolytic viruses with or without genetic alterations in combination with immune checkpoint blockade, cytokines, antigens and other oncolytic viruses as well. This review is focused on the efficacy and safety of virotherapy and the most promising combinations based on the published clinical data, rather than presenting all oncolytic virus variations, which are discussed in comprehensive literature reviews. We briefly revise the research landscape of oncolytic viruses and discuss future perspectives in virus immunotherapy, in order to provide an insight for novel strategies of cancer treatment.
... Over the past two decades, monoclonal antibodies designed to target tumor cells or improve immune system exhaustion with fewer side effects and high efficacy have rapidly increased due to increased understanding of genomic studies and technological advances [22][23][24]. It is worth noting that, in recent years, more than 33 new therapeutic antibodies are in the late stage of the clinical phase to evaluate their therapeutic effect on cancer [25]. ...
... An important factor leading to the growth of anticancer MTAs is increasing cancer incidence and mortality worldwide [26]. Conventional cancer treatments include chemotherapy, radiotherapy, and surgery that have common side effects such as fever, infection, heart failure, and allergic reactions [3,22,23]. Moreover, high efficacy and fewer side effects are another reason why MTAs are more favored [27]. ...
Background:
Monoclonal antibodies with high efficiency and specificity are one of the best strategies to diagnose and treat a variety of diseases such as cancer, autoimmunity, and inflammatory diseases. The market for monoclonal therapeutic antibodies (MTAs) has grown dramatically in the past decade.
Objective:
Given the importance of these issues, developing countries spend a high cost on importing or producing MTAs annually. This study intends to examine the market of monoclonal therapeutic antibodies in Iran and predict the future growth rate of this market using the obtained data.
Methods:
Data on the status of MTAs in the country (from 2008 to 2018) were obtained from the Food and Drug Deputy of Mazandaran University of Medical Sciences. The market status of MTAs was studied based on the dosage forms, application, and price. Then, the market outlook was predicted up to year 2025.
Results:
The results showed that 58.8% of all MTAs were humanized, and 86% of all antibody-based drugs were used to treat cancer. Sales of MTA-based medications will reach $454 million by 2025 and are projected to grow significantly in the future.
Conclusion:
Given the increasing technology of the production of MTAs and their use in targeted therapies worldwide, their consumption market in Iran is expected to grow significantly.
... Immunotherapy in cancer treatment has advanced considerably in the last few years [3][4][5], while cellular approaches like allogeneic HSCT and donor lymphocyte infusion (DLI) are since long part of routine clinical practice in the treatment of AML [6,7]. The mechanisms underlying cure in AML patients are based on the graft-versus-leukemia (GvL) effect, in which allogeneic T cells recognize target antigens on malignant cells. ...
... Immunotherapeutic treatment approaches with the goal to combine different immunotherapeutic strategies, like the combination of ICI with peptide vaccination directed against LAA, might be very interesting and could represent a further area of development for immunotherapy of malignant diseases [4,31]. ...
The efficacy of immunotherapies in cancer treatment becomes more and more apparent not only in different solid tumors but also in hematological malignancies. However, in acute myeloid leukemia (AML), mechanisms to increase the efficacy of immunotherapeutic approaches have to be further elucidated. Targeting leukemic progenitor and stem cells (LPC/LSC) by specific CTL, for instance, in an adjuvant setting or in minimal residual disease, might be an option to prevent relapse of AML or to treat MRD. Therefore, we investigated the influence of immune checkpoint inhibitors on LAA-specific immune responses by CTL against leukemic myeloid blasts and colony-forming cells including leukemic progenitor cells (CFC/LPC). In functional immunoassays like CFU/CFI (colony-forming units/immunoassays) and ELISpot analysis, we detected specific LAA-directed immune responses against CFC/LPC that are postulated to be the source population of relapse of the disease. The addition of nivolumab (anti-PD-1) significantly increases LAA-directed immune responses against CFC/LPC, no effect is seen when ipilimumab (anti-CTLA-4) is added. The combination of ipilimumab and nivolumab does not improve the effect compared to nivolumab alone. The anti-PD1-directed immune response correlates to PD-L1 expression on progenitor cells. Our data suggest that immunotherapeutic approaches have the potential to target malignant CFC/LPC and anti-PD-1 antibodies could be an immunotherapeutic approach in AML. Moreover, combination with LAA-directed vaccination strategies might also open interesting application possibilities.
... 7 In parallel, cancer treatment innovations, such as targeted therapies or immunotherapies (ITs) have changed the landscape of cancer treatment. 8,9 Anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have demonstrated their efficacy in extending survival and improving quality of life 10 in many advanced cancers, such as melanoma, lung cancer, renal cell carcinoma or head and neck cancer. [11][12][13][14] By the end of 2021, five ITs of the anti-PD-1/PD-L1 class used in monotherapy or in combination (atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab) have been approved in France in a growing number of indications, with an even increasing number of patients treated over time. ...
... The checkpoint inhibitors are used in immunotherapy of cancers but since they boost all the immune cells, and not the ones that target cancer, the overactive T cells can cause possible side effects such as fatigue, nausea, skin rash, pruritus, anorexia, diarrhoea, and breathlessness and dry cough from inflammation of the lungs. They also cause, liver, kidney and thyroid dysfunction [11,28,29]. The human immune system mounts natural endogenous response to highly immunogenic tumour cells through a series of steps, including the presenting of tumour antigens to T cells via antigen-presenting cells (APCs), priming and activation of T cells in the lymph nodes, trafficking and infiltration of T-cells into tumour beds, recognition of cancer cells by T cells, development of antigen-specific effector and memory T cells, and humoral immunity, allowing effector T cells and other endogenous immune cells as well as tumour-effective antibodies to tumour to eliminate cancer cells [30]. ...
The immune response system contributes to the body’s defence against infection, toxic or allergenic substances and is concerned with the recognition of tumour cells. In responding to a challenge the immune system is able to distinguish the body’s own cells and components(self) via the major histocompatability complex (HLA-DR) class 1 from cells that are foreign (non-self). The abnormalities of the immune response is demonstrated in the immunodeficiency diseases (congenital and acquired), the hypersensitivity reactions that may be involved in producing autoimmune diseases and the switching-off of T cell function by cancer cells. The genetic regulation of the immune system have major implications in clinical medicine as to the understanding of autoimmune disease and the idiotypic network that militates against autoimmune response and excessive immune responses. The relationship between immune function and tumour cells is highly complex but crucial to the understanding of both tumour rejection and progression mechanisms The improved knowledge of the immune system has expanded the role of immunotherapy and vaccine therapy in oncology. The article reviewed the essential immune mechanisms in health and disease, and the clinical implications.
... The checkpoint inhibitors are used in immunotherapy of cancers but since they boost all the immune cells, and not the ones that target cancer, the overactive T cells can cause possible side effects such as fatigue, nausea, skin rash, pruritus, anorexia, diarrhoea, and breathlessness and dry cough from inflammation of the lungs. They also cause, liver, kidney and thyroid dysfunction [11,29,30]. The human immune system mounts natural endogenous response to highly immunogenic tumour cells through a series of steps, including the presenting of tumour antigens to T cells via Antigen-Presenting Cells (APCs), priming and activation of T cells in the lymph nodes, trafficking and infiltration of T-cells into tumour beds, recognition of cancer cells by T cells, development of antigen-specific effector and memory T cells, and humoral immunity, allowing effector T cells and other endogenous immune cells as well as tumour-effective antibodies to tumour to eliminate cancer cells [31]. ...
The immune response system contributes to the body’s defence
against infection, toxic or allergenic substances and is concerned
with the recognition of tumour cells. In responding to a challenge
the immune system is able to distinguish the body’s own cells and
components (self) via the major histocompatability complex (HLA�DR) class 1 from cells that are foreign (non-self). The abnormalities
of the immune response is demonstrated in the immunodeficiency
diseases (congenital and acquired), the hypersensitivity reactions
that may be involved in producing autoimmune diseases and the
switching-off of T cell function by cancer cells. The genetic regu�lations of the immune system have major implications in clinical
medicine as to the understanding of autoimmune disease and the
idiotypic network that militates against autoimmune response and
excessive immune responses. The relationship between immune
function and tumour cells is highly complex but crucial to the un�derstanding of both tumour rejection and progression mechanisms.
The improved knowledge of the immune system has expanded the
role of immunotherapy and vaccine therapy in oncology. The article
reviewed the essential immune mechanisms in health and disease,
and the clinical implications.
... The immunotherapy approach harnesses the immune system to attack tumors [23,24]. As tumors can evade the immune system by suppressing or hiding ligands recognized by immune cells, immunotherapy using checkpoint inhibitors [25][26][27], chimeric antigen receptor T (CAR-T) cells [28][29][30], and cancer vaccines [31][32][33] facilitates the activation of the immune system to recognize and attack cancer cells. Adoptive cell transfer is also a type of immunotherapies using modified immune cells extracted from the patients themselves [34,35]. ...
Despite numerous efforts, the therapeutic advancement for neuroblastoma and other cancer treatments is still ongoing due to multiple challenges, such as the increasing prevalence of cancers and therapy resistance development in tumors. To overcome such obstacles, drug combinations are one of the promising applications. However, identifying and implementing effective drug combinations are critical for achieving favorable treatment outcomes. Given the enormous possibilities of combinations, a rational approach is required to predict the impact of drug combinations. Thus, CRISPR-Cas-based and other approaches, such as high-throughput pharmacological and genetic screening approaches, have been used to identify possible drug combinations. In particular, the CRISPR-Cas system (Clustered Regularly Interspaced Short Palindromic Repeats) is a powerful tool that enables us to efficiently identify possible drug combinations that can improve treatment outcomes by reducing the total search space. In this review, we discuss the rational approaches to identifying, examining, and predicting drug combinations and their impact.
... Immunotherapy boosts the immune system's ability to fight cancer cells by modulating the capacity of immune cells [1][2][3]. In the last decade, there have been giant strides in the use of immunotherapy to treat cancer, as evidenced by the approval of both monoclonal antibodies to target different immune system components and adaptive T-cell-based therapies [4]. ...
Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.
... I mmunotherapy that stimulates the immune system to target tumor cells is rapidly transforming cancer treatment (1). Although T-cell therapy and engagement have shown remarkable results, comparatively little focus has been put on directing the complement system toward tumor cells, though the complement system is known to represent a powerful cell-killing system. ...
Activation of the complement system represents an important effector mechanism of endogenous and therapeutic Abs. However, efficient complement activation is restricted to a subset of Abs due to the requirement of multivalent interactions between the Ab Fc regions and the C1 complex. In the present study, we demonstrate that Fc-independent recruitment of C1 by modular bispecific single-domain Abs that simultaneously bind C1q and a surface Ag can potently activate the complement system. Using Ags from hematological and solid tumors, we show that these bispecific Abs are cytotoxic to human tumor cell lines that express the Ag and that the modular design allows a functional exchange of the targeting moiety. Direct comparison with clinically approved Abs demonstrates a superior ability of the bispecific Abs to induce complement-dependent cytotoxicity. The efficacy of the bispecific Abs to activate complement strongly depends on the epitope of the C1q binding Ab, demonstrating that the spatial orientation of the C1 complex upon Ag engagement is a critical factor for efficient complement activation. Collectively, our data provide insight into the mechanism of complement activation and provide a new platform for the development of immunotherapies.
... High-dimensional analyses of single cells have various clinical implications, such as the detection of high-dimensional biomarkers for immunotherapy response, the precise design of low-dimensional biomarkers, an enhanced analysis of bulk sequencing data, and the advancement of our comprehension of the intricate spatial cell-cell interactions in the TME that underlie immunotherapy responses. Combination therapy is a promising treatment approach against cancer, given the rising diversity of immunotherapies accessible, as well as the customized nature of tumor heterogeneity and therapeutic resistance [124][125][126]. As a consequence, multimodal biomarker profiles will become more important in identifying the optimum therapy options for each cancer patient. ...
The complexity of the cellular and non-cellular milieu surrounding human tumors plays a decisive role in the course and outcome of disease. The high variability in the distribution of the immune and non-immune compartments within the tumor microenvironments (TME) among different patients governs the mode of their response or resistance to current immunotherapeutic approaches. Through deciphering this diversity, one can tailor patients’ management to meet an individual’s needs. Single-cell (sc) omics technologies have given a great boost towards this direction. This review gathers recent data about how multi-omics profiling, including the utilization of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (scATAC-seq), T-cell receptor sequencing (scTCR-seq), mass, tissue-based, or microfluidics cytometry, and related bioinformatics tools, contributes to the high-throughput assessment of a large number of analytes at single-cell resolution. Unravelling the exact TCR clonotype of the infiltrating T cells or pinpointing the classical or novel immune checkpoints across various cell subsets of the TME provide a boost to our comprehension of adaptive immune responses, their antigen specificity and dynamics, and grant suggestions for possible therapeutic targets. Future steps are expected to merge high-dimensional data with tissue localization data, which can serve the investigation of novel multi-modal biomarkers for the selection and/or monitoring of the optimal treatment from the current anti-cancer immunotherapeutic armamentarium.
... Immunotherapy has been a rising star in the field of tumor treatment in recent years [18], which is defined as a biological treatment using substances to stimulate or suppress the immune system, helping human body against cancer, infection, or other types of diseases according to National Cancer Institute (NCI) [19]. For cancer treatment, immunotherapy aims to generate a tumor-specific immune response to selectively eliminate tumor cells [20], which can be divided into two parts: active immunotherapy and passive immunotherapy [21,22]. The active immunotherapy induces certain immune responses against tumors by injection of exogenous antigens, such as vaccines including peptide vaccines and cell-based vaccines, while passive immunotherapy kills tumor cells by injecting exogenous immune substances without a direct activation of the body's immune system, which includes but not limited to antibody therapy and adoptive immunotherapy [23]. ...
Glioblastoma (GBM) is the most malignant CNS tumor with a highest incidence rate, and most patients would undergo a recurrence. Recurrent GBM (rGBM) shows an increasing resistance to chemotherapy and radiotherapy, leading to a significantly poorer prognosis and the urgent need for novel treatments. Immunotherapy, a rapidly developing anti-tumor therapy in recent years, has shown its potential value in rGBM. Recent studies on PD-1 immunotherapy and CAR-T therapy have shown some efficacy, but the outcome was not as expected. Tumor vaccination is the oldest approach of immunotherapies, which has returned to the research focus because of the failure of other strategies and subversive understanding of CNS. The isolation effect of blood brain barrier and the immunosuppressive cell infiltration could lead to resistance existing in all phases of the anti-tumor immune response, where novel tumor vaccines have been designed to overcome these problems through new tumor antigenic targets and regulatory of the systematic immune response. In this review, the immunological characteristics of CNS and GBM would be discussed and summarized, as well as the mechanism of each novel tumor vaccine for rGBM. And through the review of completed early-phase studies and ongoing large-scale phase III clinical trials, evaluation could be conducted for potential immune response, biosecurity and initial clinical outcome, which further draw a panorama of this vital research field and provide some deep thoughts for the prospective tendency of vaccination strategy.
... Multiple studies on active biomaterials have been conducted that specifically target immune reactions and immune cells (Sun, 2017;McCune, 2018). The use of nanotechnology as a combination of biomaterials and drugs has yielded many intriguing performances in terms of effective therapies (Chen and Mellman, 2013;Martin-Liberal et al., 2017;Oiseth and Aziz, 2017;Yu and Cui, 2018). Currently, PLGA (polylactic-co-glycolic acid) NPs, liposomes, dendrimers, and gold NPs (AuNPs) are broadly studied and used in cancer immunotherapy. ...
Over the past two decades, unique and comprehensive cancer treatment has ushered new hope in the holistic management of the disease. Cancer immunotherapy, which harnesses the immune system of the patient to attack the cancer cells in a targeted manner, scores over others by being less debilitating compared to the existing treatment strategies. Significant advancements in the knowledge of immune surveillance in the last few decades have led to the development of several types of immune therapy like monoclonal antibodies, cancer vaccines, immune checkpoint inhibitors, T-cell transfer therapy or adoptive cell therapy (ACT) and immune system modulators. Intensive research has established cancer immunotherapy to be a safe and effective method for improving survival and the quality of a patient’s life. However, numerous issues with respect to site-specific delivery, resistance to immunotherapy, and escape of cancer cells from immune responses, need to be addressed for expanding and utilizing this therapy as a regular mode in the clinical treatment. Development in the field of nanotechnology has augmented the therapeutic efficiency of treatment modalities of immunotherapy. Nanocarriers could be used as vehicles because of their advantages such as increased surface areas, targeted delivery, controlled surface and release chemistry, enhanced permeation and retention effect, etc. They could enhance the function of immune cells by incorporating immunomodulatory agents that influence the tumor microenvironment, thus enabling antitumor immunity. Robust validation of the combined effect of nanotechnology and immunotherapy techniques in the clinics has paved the way for a better treatment option for cancer than the already existing procedures such as chemotherapy and radiotherapy. In this review, we discuss the current applications of nanoparticles in the development of ‘smart’ cancer immunotherapeutic agents like ACT, cancer vaccines, monoclonal antibodies, their site-specific delivery, and modulation of other endogenous immune cells. We also highlight the immense possibilities of using nanotechnology to accomplish leveraging the coordinated and adaptive immune system of a patient to tackle the complexity of treating unique disease conditions and provide future prospects in the field of cancer immunotherapy.
... Recent studies have suggested that PD-L1 expression could be a main factor in cancer progression through inhibiting anti-cancer immune response (33,34). Indeed, many solid tumor cells can escape the host immune system by expressing PD-L1, and then activating immunosuppressive signals (35,36). Lymphoma is a malignancy of immune system cells and the role of the PD-L1 in lymphoma is more complicated. ...
Background and Aims
The clinical outcome of relapsed and refractory (RR) extranodal natural killer/T-cell lymphoma (ENKTL) is poor. It is necessary to identify RR patients in ENKTL and find novel therapeutic targets to improve the prognosis of patients with RR ENKTL.
Methods
A total of 189 ENKTL patients with effective clinical characteristics were enrolled. Paraffin specimens were collected for PD-L1 expression identification. Kaplan-Meier curve analysis was performed for survival analysis. Whole exome sequencing (WES) was performed for identifying the mutational characterization of RR and effective treatment (ET) patients.
Results
Univariate and multivariate Cox proportional hazards regression analysis showed that negative PD-L1 expression (HR = 1.132, 95% CI = 0.739-1.734, P = 0.036) was an independent predictor of poor prognosis in patients with ENKTL. The overall survival (OS) of PD-L1 positive patients was significantly higher than that of PD-L1 negative patients ( P = 0.009). Then, we added PD-L1 expression as a risk factor to the model of Prognostic Index of Natural Killer Lymphoma (PINK), and named as PINK+PD-L1. The PINK+PD-L1 model can significantly distinguish RR patients, ET patients, and the whole cohort. Moreover, our data showed that PD-L1 expression was lower than 25% in most RR patients, suggesting that RR subtypes may be associated with low expression of PD-L1 ( P = 0.019). According to the whole exome sequencing (WES), we found that the mutation frequencies of JAK-STAT ( P = 0.001), PI3K-AKT ( P = 0.02) and NF-kappa B ( P < 0.001) pathways in RR patients were significantly higher than those in ET patients.
Conclusion
Patients tend to show RR when PD-L1 expression is lower than 25%. The model of PINK+PD-L1 can stratify the risk of different groups and predict OS in ENKTL patients. The mutational profile of ENKTL patients with RR is different from that of patients with ET.
... Tumours of the brain can be treated with surgery for tumour resection, radiation (radiotherapy), chemotherapy (i.e., the use of anti-cancer drugs (cytotoxic) whose function is to damage cancer cells), treatment with alternating electric fields, targeted biological therapy (targeted therapy) targeted to tumour-specific genes, proteins, or to the tissue environment that contributes to tumour development, and immunotherapy [18,19,20] From theoretical research to experimental investigations, scientists from all fields worldwide are searching for a solution to this disease [21,22,23], [24,25,26,27,28,29,30,31,32,33,34], [35,36,37,38], and this solution can originate from several sources. Medical doctors, scientists such as biological physicists, and mathematicians are involved in cancer research There are numerous possible approaches to cancer treatment. ...
In this study, we investigated a mathematical model for chemoimmunotherapy (a combination of chemotherapy and immunotherapy) for brain cancer. In most cases, the standard protocol for cancer treatment is fixed in terms of treatment time intervals and dosages. We offer a wide range of non-fixed protocols, which essentially vary in terms of time intervals and dosages (i.e., personalised medicine). The functions that describe this treatment are explicit and analytical. Hence, the parameters of the function can be easily changed and a new protocol can be obtained. We compared different protocols and obtained an optimal solution. In addition, we applied the singular perturbed vector field (SPVF) method to determine the hierarchy of the system of equations, which enabled us to identify the equilibrium points of the mathematical model and investigate their stability.
... The introduction of immune-checkpoint inhibitors (ICIs) over the last decade has represented a major development in cancer treatment (1). Single-agent or combination ICI therapies have been approved for many advanced cancers, and their clinical application continues to grow (2). ...
Objectives
Extrapolation is often required to inform cost-effectiveness (CE) evaluations of immune-checkpoint inhibitors (ICIs) since survival data from pivotal clinical trials are seldom complete. The objectives of this study were to evaluate the accuracy of estimates of long-term overall survival (OS) predicted in French CE assessment reports of ICIs, and to identify models presenting the best fit to the observed long-term survival data.
Methods
A systematic review of French assessment reports of ICIs in the metastatic setting since inception until May 2020 was performed. A targeted literature review was conducted to collect associated extended follow-up of randomized controlled trials (RCTs) used in the CE assessment reports. Difference between projected and observed OS was calculated. A range of standard parametric and spline-based models were applied to the extended follow-up data from the RCT to determine the best-fitting survival models.
Results
Of the 121 CE assessment reports published, 11 reports met the inclusion criteria. OS was underestimated in 73 percent of the CE assessment reports. The mean relative difference between each source was −13 percent (median: −15 percent; IQR: −0.4 to 26 percent). Models providing the best fit were those that could reflect nonmonotonic hazards.
Conclusions
Based on the available data at the time of submission, longer-term survival of ICIs was not fully captured by the extrapolation models used in CE assessments. Standard and flexible parametric models which can capture nonmonotonic hazard functions provided the best fit to the extended follow-up data. However, these models may still have performed poorly if fitted to survival data available at the time of submission to the French National Authority for Health.
... Vaccines that have been tested clinically or preclinically are mostly strategies by a rational selection of the encoded antigen(s) and then by using combination therapies to prevent the immunosuppressive cells infiltration for immunosuppression in the tumor microenvironment [134]. The different types of cancer vaccines that have been shown the ability to arrest the tumor progression by expressing immune response under preclinical or clinical trials are (a) DNA and RNA vaccines, (b) viral or bacterial based vaccines, (c) cell-based vaccines, (d) protein/peptide vaccines, and (e) gene-based vaccines [135][136][137][138][139][140]. ...
Abstract
Cancer vaccines, also called therapeutic vaccines, improve the body's standard defense against cancer. Usually, the cancer vaccine is provided to the patient with already detected cancer. Immunotherapy is aimed more directly at cancer cells compared to conventional surgery, chemotherapy, or radiotherapy, offering patients the potential to provide improved reactions, enhance life-quality, or even cure the disease. Cancer vaccines might be designed to target tumor-associated antigens (TAAs), cancer germline antigens, virus-related antigens, or tumor-specific antigens (TSAs), which are also widely recognized as neoantigens. Sipuleucel-T (Provenge) and Talimogene laherparepvec (T-VEC) are the two FDA-approved vaccines currently being utilized for advanced prostate cancer and advanced melanoma skin cancer, respectively. Clinical trials are essential for learning more about cancer vaccines. Researchers are testing vaccines for several types of cancers, including bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, lung cancer, and many more. This chapter discusses the literature and data on the value and use of cancer vaccines. Although cancer vaccines as a single therapy are not sufficient to declare a complete victory over this deadly disease until now, it must be a comprehensive approach and existing treatments on the concept of cancer management.
... 6,9 The anti-PD-1 and anti-PD-L1 drugs have been approved by the Food and Drug Administration. 34 Galectin-9 ...
Pancreatic adenocarcinoma (PAAD) remains an extremely fatal malignancy with high mortality rate worldwide. This study focuses on the roles of ubiquitin specific peptidase 10 (USP10) and Cyr61 in macrophage polarization, immune escape, and metastasis of PAAD. USP10 showed a positive correlation with YAP, each of which was suggested highly expressed in PAAD and indicate poor patient prognosis according to TCGA-PAAD database. USP10 knockdown increased ubiquitination and degradation of YAP1, which further decreased the PD-L1 and Galectin-9 expression, suppressed immune escape, and reduced the proliferation and metastasis of PAAD cells in vitro and in vivo. Cyr61, a downstream factor of YAP1, was overexpressed in PAAD cells after USP10 silencing for rescue experiments. Overexpression of Cyr61 restored the PD-L1 and Galectin-9 expression in cells and triggered M2 polarization of macrophages, which enhanced the immune escape and maintained the proliferation and metastasis ability of PAAD cells. In conclusion, this work demonstrates that USP10 inhibits YAP1 ubiquitination and degradation to promote Cyr61 expression, which induces immune escape and promotes growth and metastasis of PAAD.
... Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.15,000 x g. ...
Cholangiocarcinoma is a form of hepatobiliary cancer with an abysmal prognosis. Despite advances in our understanding of cholangiocarcinoma pathophysiology and its genomic landscape, targeted therapies have not yet made a significant impact on its clinical management. The low response rates of targeted therapies in cholangiocarcinoma suggest that patient heterogeneity contributes to poor clinical outcome. Here we used mass spectrometry–based phosphoproteomics and computational methods to identify patient-specific drug targets in patient tumors and cholangiocarcinoma-derived cell lines. We analyzed 13 primary tumors of patients with cholangiocarcinoma with matched nonmalignant tissue and 7 different cholangiocarcinoma cell lines, leading to the identification and quantification of more than 13,000 phosphorylation sites. The phosphoproteomes of cholangiocarcinoma cell lines and patient tumors were significantly correlated. MEK1, KIT, ERK1/2, and several cyclin-dependent kinases were among the protein kinases most frequently showing increased activity in cholangiocarcinoma relative to nonmalignant tissue. Application of the Drug Ranking Using Machine Learning (DRUML) algorithm selected inhibitors of histone deacetylase (HDAC; belinostat and CAY10603) and PI3K pathway members as high-ranking therapies to use in primary cholangiocarcinoma. The accuracy of the computational drug rankings based on predicted responses was confirmed in cell-line models of cholangiocarcinoma. Together, this study uncovers frequently activated biochemical pathways in cholangiocarcinoma and provides a proof of concept for the application of computational methodology to rank drugs based on efficacy in individual patients.
Significance
Phosphoproteomic and computational analyses identify patient-specific drug targets in cholangiocarcinoma, supporting the potential of a machine learning method to predict personalized therapies.
... To date there are five different classes of cancer immunotherapies, many of which have been around for decades [9]. These include immunomodulators, antibody targeted cell elimination, vaccines, oncolytic viruses, and cell-based immunotherapies [9][10][11][12]. The first cell-based immunotherapy to treat hematologic cancers was performed at the University of Minnesota in 1970s in the form of bone marrow transplantation [13]. ...
Nanotechnology, photonics, and immunotherapy are far-reaching technologies with the potential to revolutionize the field of cancer diagnostics and therapeutics. While each technology has limitations in cancer treatment, they can be synergized to exert profound impact on the balance and modulation of immunoediting in tumor microenvironment (TME) and in the entire host immune system. We provide our perspectives on how nano-photo-immuno interactions can be used as an effective therapy, particularly when combined with other treatment modalities, such as checkpoint immune therapy, chemotherapy, and TME modulation, to provide a long-term, tumor-specific immunity against tumor metastasis and tumor recurrence.
... Cancer immunotherapy has become an appealing and attractive strategy among different therapeutic options over the past years and has shown efficacy against malignancies. 1 For decades, antibodies have been a standard component of cancer therapy, and efforts accordingly continue to build improved cancer therapeutics. 2 The current era of successful antibody-based therapeutics began with the development of techniques that allowed for genetic or chemical modification of naked antibodies and produced molecules with multifunctional strategies to overcome potential tumor resistance. ...
Various antibody-redirected immunotherapeutic approaches, including antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor-T (CAR-T) cells, have been devised to produce specific activity against various cancer types. Using genetically encoded unnatural amino acids, we generated a homogeneous Her2-targeted ADC, a T cell-redirected bsAb, and a FITC-modified antibody capable of redirecting anti-FITC CAR-T (switchable CAR-T; sCAR-T) cells to target different Her2-expressing breast cancers. sCAR-T cells showed activity against Her2-expressing tumor cells comparable to that of conventional anti-Her2 CAR-T cells and superior to that of ADC- and bsAb-based approaches. To prevent antigen escape, we designed bispecific sCAR-T cells targeting both the Her2 receptor and IGF1R, which showed an overall improved activity against cancer cells with low Her2 expression. This study increases our understanding of various explored cancer therapeutics and underscores the efficient application of sCAR-T cells as a promising therapeutic option for breast cancer patients with low or heterogeneous antigen expression.
... Several kinds of immunotherapies have been under investigation in recent years. The manipulation of immune checkpoints, in particular cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), known as an immune checkpoint inhibitor (ICI), has been of particular interest in this regard [42]. ...
Aging is a well-recognized risk factor for the development of cancer. The incidence of new cancer diagnoses has increased globally given the rising senior population. Many hypotheses for this increased risk have been postulated over decades, including increased genetic and epigenetic mutations and the concept of immunosenescence. The optimal treatment strategies for this population with cancer are unclear. Older cancer patients are traditionally under-represented in clinical trials developed to set the standard of care, leading to undertreatment or increased toxicity. With this background, it is crucial to investigate new opportunities that belong to the most recent findings of an anti-cancer agent, such as immune-checkpoint inhibitors, to manage these daily clinical issues and eventually combine them with alternative administration strategies of antiblastic drugs such as metronomic chemotherapy.
... These checkpoint inhibitors, anti-PD-1 MAbs such as nivolumab or pembrolizumab-or in this case tislelizumab; anti-PD-L1 MAbs such as atezolizumab, avelumab or durvalumab; and CTLA-4 inhibitors like ipilimumab or tremelimumab, may achieve durable as well as clinically meaningful responses in patients with different tumour types, including melanoma, nonsmall-cell lung cancer, renal cell carcinoma, bladder cancer, Hodgkin's lymphoma and any cancer with high microsatellite instability status. [29][30][31] Clinical data on the use of checkpoint inhibitors in patients with rare tumours are accumulating rapidly and several immunotherapy trials are currently open. Among these trials, the DART (dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors) trial 32 is worth discussing here because it is testing the combined use of ipilimumab and nivolumab for rare cancers. ...
Myxopapillary ependymoma (MPE) is a rare glial tumour mainly located in the areas of the conus medullaris, cauda equina and filum terminale of the spinal cord. Ectopic MPE tends to behave more aggressively and distant metastases are often seen. Unfortunately, no standard treatment options are established as only small series of treated patients and a few reported cases are available in the literature. We report the case of a 25-year-old woman who was initially diagnosed with a metastatic MPE, with multiple bilateral lung metastases. She was treated with an investigational monoclonal antibody antiprogrammed cell death protein 1, called tislelizumab (BGB-A317), following surgical resection of the perisacral primary mass. The response was long- lasting and side effects nil. Immunotherapy is a treatment modality to be considered in patients with rare tumours.
... Cancers are able to evade host antitumor immune responses through immune escape mechanisms. Immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD-1)/programmed death ligand 1orcytotoxic T-lymphocyte-associated protein 4, interrupt the mechanisms of immune resistance and exhibit durable and powerful antitumor activity in specific subsets of patients across several types of tumor (6). ...
Herpesvirus entry mediator (HVEM) displays dual signals in T-cell activation according to the ligands and intracytoplasmic effectors it interacts with. High HVEM expression may play an immunosuppressive role in several malignancies. The present study investigated the clinical impact of HVEM on intrahepatic cholangiocarcinoma (ICC), including its prognostic value, and association with clinicopathological features and immune status. The clinical data of 102 consecutive patients with ICC who underwent surgical treatment from January 2012 to December 2017 were collected. The expression of HVEM and different types of tumor-infiltrating lymphocytes (TILs) were investigated in ICC tissue samples by immunohistochemical staining. HVEM expression was detected in the tumor tissues of 92 (90.2%) patients with ICC. Patients with high HVEM expression were more likely to have increased peripheral blood lymphocyte (PBL) concentrations (P=0.031), decreased CEA (P=0.036), low TNM stage (P=0.043) and high frequencies of small-duct histological type (P=0.021) and BAP1 retained expression (P=0.010). Survival analysis showed that high HVEM expression was a favorable independent predictor of overall postoperative survival (P=0.034, hazard ratio=0.486, 95% confidence interval=0.249-0.945). In addition, no significant association of HVEM expression with CD4+ (P=0.512), CD8+ (P=0.750) or CD45RO+ (P=0.078) TILs was identified in the ICC tissues. These results indicate that HVEM may serve as a favorable prognostic marker for ICC. Furthermore, co-stimulatory signals from HVEM may play a dominant role in the progression of ICCs, which can be explained by an increase in the number of PBLs rather than a change in the number of TILs. However, the function of the HVEM network in ICC progression is complex and requires further study.
... Activating antitumor immune responses, especially the T cellmediated immune responses, is one of the effective strategies for cancer immunotherapy. 4,118 Due to the immunosuppressive TME, the body is often unable to successfully initiate antitumor immune responses. 119 According to the biological characteristics of the immune response, the establishment of an effective anti-tumor immune response usually requires the release of tumor antigens, activation of the innate immune system, maturation of APCs, the activation and proliferation of tumor-specific T lymphocytes, T cell infiltration in the tumor site and specific recognition of tumor cells. ...
Cancer immunotherapy provides an effective way to deal with cancer. Although immunotherapy strategies have shown encouraging therapeutic effects, the inherent limitations of immunotherapy, such as multiple tumor immune evasion methods, low responsive rate, and systemic toxicity, still hinder its clinical applications. In recent decades, nanomaterials are considered promising in cancer immunotherapy since they can realize targeted delivery and interact with the immune system to induce or enhance the antitumor immune responses. Among them, organic/inorganic nanocomposites are ideal candidates for cancer immunotherapy since they could combine both advantages of organic and inorganic components. Multifunctional organic/inorganic nanocomposites could help overcome the shortcomings of current cancer immunotherapy, and realize the combination of immunotherapy and other therapeutic strategies with synergistic antitumor effect. Herein, we review the recent progress of organic/inorganic nanocomposites designed for cancer immunotherapy. The immunotherapy strategies of nanocomposites are summarized from the perspective of achieving immune enhancement. The challenges of nanocomposites in cancer immunotherapy are also discussed.
... The manipulation and education of the immune system for targeting and eliminating cancer cells has been viewed as a crucial goal of cancer therapy for decades [1][2][3]. The recent introduction of monoclonal antibodies (mAbs) blocking immune checkpoint molecules, such as programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), in clinical practice, has been a clear success, highlighting the potential of immunotherapy in the oncology field [4,5]. ...
Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their development, regulation and heterogeneity. We also address the role of this functionally thrilling DC subset in anti-tumor immune responses and the most recent efforts to apply it in cancer immunotherapy.
... 6,7 In the latest years, immunotherapy with checkpoints inhibitors has represented one of the major breakthroughs in anticancer research, revolutionizing both the therapeutic paradigm and the life expectancy of a large series of tumors, including lung cancer, melanoma, and renal cell carcinoma (RCC). 8 However, only limited prospective data about the activity and safety of immunotherapy are available for elderly patients. [9][10][11][12] Therefore, we conducted a systemic review and meta-analysis of randomized controlled trials to evaluate the efficacy of immune checkpoint inhibitors (ICIs) according to age. ...
Limited prospective data about the activity of immune checkpoint inhibitors (ICIs) are available for elderly patients. The aim of our analysis was to determine the relative efficacy of ICIs versus available standard therapies [standard of care (SOC)] in subgroups defined by patients' age. Searching the MEDLINE/PubMed, Cochrane Library, and American Society of Clinical Oncology (ASCO) Meeting abstracts randomized clinical trials were identified. Data extraction was conduced according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The measured outcome was overall survival (OS). Twenty-nine randomized clinical trials (18,839 patients) were selected. As for the distribution of patients by age, all but 3 of the selected studies considered young the patients younger than 65 years (n=10,832) and elderly those with 65 years and older (n=7723); 7 studies identified a third subgroup of very elderly patients aged 75 years and above (n=421). In elderly and very elderly patients ICIs significantly reduced the risk of death by 23% compared with SOC [hazard ratio (HR), 0.77; P<0.00001)]. On the contrary, a lack of a survival advantage of immunotherapy was observed in the subgroup of very elderly patients (HR, 0.85; P=0.39). When comparing the efficacy of ICIs between the 2 subpopulations (elderly vs. young), no significant difference in OS was observed (HR, 0.76; P=0.66). ICIs prolonged OS compared with SOC in both elderly and young patients affected by lung cancer, melanoma, and renal carcinoma, regardless of the age. In conclusion, ICIs (as monotherapy or combinations) significantly improved OS compared with SOC in both young and elderly patients with advanced cancers, regardless of the tumor type. The magnitude of this benefit is debated in patients aged 75 years and above.
... Immunotherapy means a method of treating diseases by managing the native immune system of the body. As a relatively novel therapeutic strategy, immunotherapy has received increasing attention due to its low potential side effects and high specificity (Martin-Liberal et al., 2017). For example, cancer immunotherapy has made great progress in recent decades, especially for the therapies of recurrent and metastatic cancer (Sharma and Allison, 2015;Young, 2017;Li et al., 2019). ...
Immunotherapy has received increasing attention due to its low potential side effects and high specificity. For instance, cancer immunotherapy has achieved great success. CpG is a well-known and commonly used immunotherapeutic and vaccine adjuvant, but it has the disadvantage of being unstable and low in efficacy and needs to be transported through an effective nanocarrier. With perfect structural programmability, permeability, and biocompatibility, DNA nanostructures are one of the most promising candidates to deliver immune components to realize immunotherapy. However, the instability and low capability of the payload of ordinary DNA assemblies limit the relevant applications. Consequently, DNA nanostructure with a firm structure, high drug payloads is highly desirable. In the paper, the latest progress of biostable, high-payload DNA nanoassemblies of various structures, including cage-like DNA nanostructure, DNA particles, DNA polypods, and DNA hydrogel, are reviewed. Cage-like DNA structures hold drug molecules firmly inside the structure and leave a large space within the cavity. These DNA nanostructures use their unique structure to carry abundant CpG, and their biocompatibility and size advantages to enter immune cells to achieve immunotherapy for various diseases. Part of the DNA nanostructures can also achieve more effective treatment in conjunction with other functional components such as aPD1, RNA, TLR ligands.
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that maintains normal tissues and cell signaling pathways. EGFR is overactivated and overexpressed in many malignancies, including breast, lung, pancreatic, and kidney. Further, the EGFR gene mutations and protein overexpression activate downstream signaling pathways in cancerous cells, stimulating the growth, survival, resistance to apoptosis, and progression of tumors. Anti‐EGFR therapy is the potential approach for treating malignancies and has demonstrated clinical success in treating specific cancers. The recent report suggests most of the clinically used EGFR tyrosine kinase inhibitors developed resistance to the cancer cells. This perspective provides a brief overview of EGFR and its implications in cancer. We have summarized natural products‐derived anticancer compounds with the mechanistic basis of tumor inhibition via the EGFR pathway. We propose that developing natural lead molecules into new anticancer agents has a bright future after clinical investigation.
Cancer is now regarded as one of the significant public health concerns, and it is predicted to overtake cardiovascular diseases in 2060. Accordingly, there is a need for new, powerful medications to decrease the impact of cancer. Herein, metastatic tumors can be prevented or eliminated using preventative and therapeutic cancer vaccinations, especially cell-based types. However, further studies are needed in such a field. Therefore, the authors have reviewed the significance of cancer prevention, treatment, and management measures, particularly the use of cell-based vaccines.
In order to find research on cell-based vaccinations and cancer therapies, we searched the literature using a combination of keywords to obtain publications published in PubMed, Scopus, and Web of Science between the years 2000 and 2023. Relevant and highly referenced articles were selected for this list.
In this review, we discuss the different types of cancer vaccines especially cell-based types. Further, we summarize related preclinical and clinical studies and also the ethical considerations. Present studies confirm the beneficial results of cell-based vaccines.
Advancements of cancer management and immunotherapy have successfully elicited anti-cancer immune responses using chimeric antigen receptor (CAR)-T cells treatment, natural killer (NK) cell therapy, CAR-NK cell therapy, and cell-based vaccines.
Research has shown that powerful drugs are needed to decrease the consequences of cancer. In recent years, many types of immunotherapy have made considerable advancements in the treatment of cancer. These consist of NK cell treatment, CAR-NK cells, and CAR-T cell therapy. Recently, advancements in cancer vaccines, such as immunizations based on cells, have been made. Spreading cancers can now be totally prevented or halted thanks to prophylactic and cancer-specific vaccines. However, further research is needed to understand and progress in this area of treatment fully.
Background:
The MISSION and CHOICE Acts expanded the Veterans Health Administration's (VA) capacity to purchase immunotherapy services for VA patients from community-based providers. Our objective was to identify predictors of community-based immunotherapy treatment, and assess differences in cost and utilization across community treatment settings METHODS: We examined claims for 21,257 patients who started immunotherapy treatment between 2015 and 2020. We assessed growth in VA community-based immunotherapy care, predictors of community-based immunotherapy treatment using multivariable logistic regression based on patients' sociodemographic and clinical characteristics. We compared utilization and costs among those who received community-based immunotherapy services in hospital outpatient departments (HOPDs) versus physician office settings (POs).
Results:
The proportion of community-based immunotherapy in the VA increased from 5.3% in 2015 to 32.1% in 2020, with total annual costs of immunotherapy growing from $6.1 million to $187 million. Older, married, and rural patients and those with more comorbidities were more likely than younger, single, or urban patients to be treated in the community. Black patients were more likely to be treated in the VA. Respiratory Cancer was the most common cancer type in both settings. Among community immunotherapy patients, we observed no meaningful differences in the number of units administered, the unit drug costs, or the cost per immunotherapy visit between POs and HOPDs.
Conclusion:
Drug costs did not differ widely across HOPDs and POs among VA patients who receive community-based immunotherapy.
Background:
T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a vital immune checkpoint that regulates the immune response. However, the specific role of TIM3 in patients with colorectal cancer (CRC) have rarely been studied. In this study, we investigated the effect of TIM3 on CD8+ T cells in CRC and explored the mechanism of TIM3 regulation in tumor microenvironment (TME).
Methods:
Peripheral blood and tumor tissues of patients with CRC were collected to evaluate TIM3 expression using flow cytometry. Cytokines in the serum of healthy donors and patients with early- and advanced-stage CRC were screened using a multiplex assay. The effects of interleukin-8 (IL8) on TIM3 expression on CD8+ T cells were analyzed using cell incubation experiments in vitro. The correlation between TIM3 or IL8 and prognosis was verified using bioinformatics analysis.
Results:
TIM3 expression on CD8+ T cells was obviously reduced in patients with advanced-stage CRC, whereas a lower TIM3 expression level was associated with poorer prognosis. Macrophage-derived IL8, which could inhibit TIM3 expression on CD8+ T cells, was significantly increased in the serum of patients with advanced CRC. In addition, the function and proliferation of CD8+ and TIM3+CD8+ T cells were inhibited by IL8, which was partly depending on TIM3 expression. The inhibitory effects of IL8 were reversed by anti-IL8 and anti-CXCR2 antibodies.
Conclusions:
In summary, macrophages-derived IL8 suppresses TIM3 expression on CD8+ T cells through CXCR2. Targeting the IL8/CXCR2 axis may be an effective strategy for treating patients with advanced CRC.
Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and its corresponding ligand PD-L1 are being increasingly used for a wide variety of cancers, including refractory sarcomas. Autoimmune hepatitis is a known side effect of ICIs, and is typically managed with broad, non-specific immunosuppression. Here, we report a case of severe autoimmune hepatitis occurring after anti-PD-1 therapy with nivolumab in a patient with osteosarcoma. Following prolonged unsuccessful treatment with intravenous immunoglobulin, steroids, everolimus, tacrolimus, mycophenolate, and anti-thymoglobulin, the patient was eventually treated with the anti-CD25 monoclonal antibody basiliximab. This resulted in prompt, sustained resolution of her hepatitis without significant side effects. Our case demonstrates that basiliximab may be an effective therapy for steroid-refractory severe ICI-associated hepatitis.
In recent years, nanoscale or microscale functional materials derived from DNA have shown great potential for immunotherapy as superior delivery carriers. DNA nanostructures with excellent programmability and addressability enable the precise assembly of molecules or nanoparticles. DNA hydrogels have predictable structures and adjustable mechanical strength, thus being advantageous in controllable release of cargos. In addition, utilizing systematic evolution of ligands by exponential enrichment technology, a variety of DNA aptamers have been screened for specific recognition of ions, molecules, and even cells. Moreover, a wide variety of chemical modifications can further enrich the function of DNA. The unique advantages of functional DNA materials make them extremely attractive in immunomodulation. Recently, functional DNA materials-based immunotherapy has shown great potential in fighting against many diseases like cancer, viral infection, and inflammation. Therefore, in this review, we focus on discussing the progress of the applications of functional DNA materials in immunotherapy; before that, we also summarize the characteristics of the functional DNA materials descried above. Finally, we discuss the challenges and future opportunities of functional DNA materials in immunomodulatory therapy.
Le cancer est la première cause de mortalité en France. Les Cholangiocarcinomes (CCAs) ou cancers des voies biliaires représentent 3% de l’ensemble des cancers digestifs. Le CCA intrahépatique avec 10 à 20 % de l’ensemble, est derrière l’hépatocarcinome, la deuxième tumeur primitive maligne du foie. La bile est un fluide stérile biologique, synthétisé dans le foie, hébergé dans la vésicule biliaire et libéré dans le duodénum après la prise alimentaire. Les populations microbiennes des différentes parties du tractus gastro-intestinal des mammifères (estomac, intestin grêle, colon, selles) ont été étudiées. Des changements dans le microbiote humain ont été associés au développement de cancer colorectal, du pancréas et du poumon. Dans la plupart des séries étudiées le mécanisme reliant le microbiote à la carcinogenèse semble être de type épigénétique. La carcinogenèse biliaire est mal connue, les caractéristiques génétiques des individus et les facteurs environnementaux y jouent un rôle prépondérant. La caractérisation du microbiote biliaire n’a été abordée que de façon fragmentaire jusqu’à présent. Nous avons caractérisé le microbiote biliaire chez des patients atteints du CCA extra-hépatique et chez des sujets témoins sans tumeurs. Des échantillons de biles ont été prélevés par la Cholangiographie pancréatique rétrograde par voie endoscopique CPRE chez 28 patients atteints de CCA sporadiques et 47 sujets témoins (porteurs de calculs biliaires).La bile a été soumise aux extractions d’ADN bactérien ainsi qu’à la caractérisation de méthylation du génome humain grâce aux séquençage d’ARN16s bactérien et des puces de méthylation (Illumina). De plus, les profils de méthylation des gènes ont été caractérisés dans des échantillons tissulaires d’adénocarcinomes pancréatique et de CCAs.Nous avons pu montrer une dysbiose biliaire associées aux CCAs, identifié une signature népigénétique liée aux CCAs dont nous avons distingué la spécificité versus celle des cellules mononuclées du sang périphérique (PBMC). Deux gènes candidats ont ainsi été sélectionnés à l’issu d’analyses de puces des méthylations et leurs expressions ont été ensuite étudiées par la technique d’immunohistochimie (IHC) dans les tissus tumoraux de CCAs intra- et extra-hépatiques et d’adénocarcinome pancréatique. Nous avons conclu sur une possible relation entre la dysbiose biliaire et le niveau d’expression des deux gènes par le phénomène de dysméthylation. Ces résultats pourraient avoir un impact diagnostique et devenir des cibles thérapeutiques.
T cells require a co‐stimulatory signal in addition to T‐cell receptor (TCR) stimulation to achieve full activation. While most studies focus on the co‐stimulatory receptor CD28, little is known about the role of the other co‐stimulatory receptors in T‐cell signaling. A deeper understanding of how co‐stimulatory receptor signaling cooperates with TCR signaling could improve the ability to control T‐cell function and benefit the design of T‐cell based immunotherapies. Artificial antigen presenting cells (aAPCs) enable tight control over the signals given to T cells. In this study, filamentous polyisocyanopeptide (PIC) polymers (immunofilaments) are used as nanosized aAPCs to study the role of the engagement of six distinct co‐stimulatory molecules on human T‐cell phenotype, function, and fate in the context of TCR signaling. The immunofilaments highlight important roles for CD28 and CD2 signaling in T‐cell priming, proliferation, cytokine production, and multifunctionality. Taken together, this work provides insight into the role of combined TCR and co‐stimulation on T‐cell phenotype, function, and fate using immunofilaments. Notably, the findings on the roles of co‐stimulatory molecule function can be used for the rational design of future cancer immunotherapies.
Recent advances in cancer immunotherapies show promise for revolutionizing the oncologic treatment of both solid and hematologic malignancies. While progress has been made in understanding immunotherapy mechanisms of action in laboratory investigations and preclinical models, there remain significant gaps in knowledge of how therapies in this class operate in patients. A better understanding of the distribution and dynamic action of cancer immunotherapies in patients aims to support patient stratification, earlier evaluation of treatment response and toxicities, and integration with other cancer treatment modalities. Noninvasive imaging tools offer influential contributions to guide the evaluation of cancer immunotherapy for these purposes. In this chapter, we review clinically relevant imaging modalities that are being developed and used to evaluate cancer immunotherapy. Image-guided approaches to assess the innate and adaptive immune system, as well as adoptive cell therapies, will be described. Finally, image-guided interventional approaches to guide the directed delivery of immunotherapies will also be outlined.
Cholangiocarcinoma (CCA) includes a group of different epithelial cancers with features of biliary tract differentiation arising from any tract of the biliary tree. Histologically, they usually are adenocarcinomas. It is a rare cancer accounting about 3% of all gastrointestinal malignancies. Based on its anatomical location, CCA is classified as intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA). Currently, the three types of CCA are considered as distinct cancers since different pathogenic and management features. Cholangiocarcinomas are aggressive tumours, often diagnosed at advanced stages. Most cases are sporadic but conditions leading to chronic inflammation and cholestasis have been recognized as risk factors. Diagnosis needs a multimodal approach, mixing imaging, endoscopy, laboratory tests, including onco-biomarkers, and pathology. Surgical resection with histologically negative margins is the only curative treatment, although it is possible only for few patients; unfortunately, recurrence is frequent. Likewise, liver transplantation is an option for a small subset of selected patients suffering from pCCA. Generally, prognosis is poor for most patients. Desmoplastic nature, highly variable genetics, interaction with a rich tumour microenvironment, all contribute to the resistance of therapy. Advances in targeted-, radio- and immunotherapy will lead to improvement in survival.
Mycophenolate mofetil resulted in rapid improvement of steroid‐refractory immune‐related adverse event hepatitis, induced by nivolumab plus ipilimumab.
Advances in molecular biology, microfluidics and bioinformatics have empowered the study of thousands or even millions of individual cells from malignant tumours at the single-cell level of resolution. This high-dimensional, multi-faceted characterization of the genomic, transcriptomic, epigenomic and proteomic features of the tumour and/or the associated immune and stromal cells enables the dissection of tumour heterogeneity, the complex interactions between tumour cells and their microenvironment, and the details of the evolutionary trajectory of each tumour. Single-cell transcriptomics, the ability to track individual T cell clones through paired sequencing of the T cell receptor genes and high-dimensional single-cell spatial analysis are all areas of particular relevance to immuno-oncology. Multidimensional biomarker signatures will increasingly be crucial to guiding clinical decision-making in each patient with cancer. High-dimensional single-cell technologies are likely to provide the resolution and richness of data required to generate such clinically relevant signatures in immuno-oncology. In this Perspective, we describe advances made using transformative single-cell analysis technologies, especially in relation to clinical response and resistance to immunotherapy, and discuss the growing utility of single-cell approaches for answering important research questions.
Cytotoxic chemotherapeutics (CHTs) have been the backbone cancer therapy for many years. Recently, a rapidly growing body of evidence has demonstrated the interdependence of cancer genetics, epigenetics, and immunology, giving rise to the generation of new promising compounds. The development of new molecularly targeted agents (MTAs), immune checkpoint-targeted monoclonal antibodies (ICT mAbs), and epigenetic drugs (EPDs) has increased the ready-to-use arsenal for patients with different cancers, but at the same time, has resulted in many substantial changes in clinical trial design, altering the early drug development (EDD) landscape. Despite sharing common developmental principles, the significant differences in their mechanisms of action (MoAs) have led researchers to reconsider previous assumptions regarding the design and execution of Phase I clinical trials (Ph1), leading to the recognition of four established paradigms in oncology. In this chapter, we review drug development evolution with a broad view of the major differences in EDD between these four paradigms, namely CHTs, MTAs, ICT mAbs, and EPDs, addressing many of the controversial issues and challenges that helped shape them. Only a comprehensive view of their main characteristics will enable successful design of future therapeutic options.
The recent success of immunotherapies has highlighted the power of leveraging the immune system in the fight against cancer. In order for most immune‐based therapies to succeed, T cell subsets with the correct tumor‐targeting specificities must be mobilized. When such specificities are lacking, providing the immune system with tumor antigen material for processing and presentation is a common strategy for stimulating antigen‐specific T cell populations. While straightforward in principle, experience has shown that manipulation of the antigen presentation process can be incredibly complex, necessitating sophisticated strategies that are difficult to translate. Herein, the design of a biomimetic nanoparticle platform is reported that can be used to directly stimulate T cells without the need for professional antigen‐presenting cells. The nanoparticles are fabricated using a cell membrane coating derived from cancer cells engineered to express a co‐stimulatory marker. Combined with the peptide epitopes naturally presented on the membrane surface, the final formulation contains the necessary signals to promote tumor antigen‐specific immune responses, priming T cells that can be used to control tumor growth. The reported approach represents an emerging strategy that can be used to develop multiantigenic, personalized cancer immunotherapies.
Next-generation sequencing of solid tumors has revealed variable signatures of immunogenicity across tumors, but underlying molecular characteristics driving such variation are not fully understood. While expression of endogenous retrovirus (ERV)-containing transcripts can provide a source of tumor-specific neoantigen in some cancer models, associations between ERV levels and immunogenicity across different types of metastatic cancer are not well established. We performed bioinformatics analysis of genomic, transcriptomic and clinical data across an integrated cohort of 199 metastatic breast, colorectal and pancreatic ductal adenocarcinoma (PDAC) patient tumors. Within each cancer type, we identified a subgroup of viral mimicry tumors in which increased ERV levels were coupled with transcriptional signatures of autonomous antiviral response and immunogenicity. In addition, viral mimicry colorectal and pancreatic tumors showed increased expression of DNA demethylation gene TET2. Taken together, these data demonstrate the existence of an ERV-associated viral mimicry phenotype across three distinct metastatic cancer types, while indicating links between ERV abundance, epigenetic dysregulation and immunogenicity.
The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or loco-regional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.
Background
The prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptably low. This study aimed to determine the efficacy, safety and predictive biomarkers of the immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs.
Methods
In this open-label, single-arm, phase II trial, a chemotherapy and immunotherapy combination consisting of gemcitabine 1000 mg/m ² , cisplatin 75 mg/m ² and nivolumab 3 mg/kg was administered every 3 weeks for up to six cycles. Maintenance treatment with gemcitabine plus nivolumab was administered to patients achieving disease control following the combination therapy. The primary outcome was the objective response rate. Secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). The exploratory objective was to assess biomarkers for predicting clinical response and prognosis.
Results
Thirty-two patients with a median age of 60 (range 27–69) years were enrolled. As of September 31, 2019, the median follow-up was 12.8 (95% CI 10.8 to 14.8) months. Twenty-seven response-evaluable patients received a median of 4 (IQR, 3–6) cycles of combination therapy, of whom 15 (55.6%) patients achieved an objective response, including 5 (18.6%) with a complete response (CR), and the DCR was 92.6%. Of the six patients in cohort A who were resistant to gemcitabine-based or cisplatin-based chemotherapy, one achieved CR and one achieved partial response. Thirteen of 21 chemotherapy-naive patients (61.9%) in cohort B achieved an objective response. The median PFS of all patients in cohorts A+B was 6.1 months. The median OS was 8.5 months, with a 33.3% 12-month OS rate. The most frequent grade 3 or higher adverse events were thrombocytopenia (56%) and neutropenia (22%). Fitness might be a biomarker for predicting clinical response. On-therapy changes in serum soluble FasL, MCP-1 and interferon-γ were correlated with prognosis.
Conclusions
Nivolumab in combination with gemcitabine and cisplatin offers promising efficacy and a manageable safety profile for patients with advanced BTCs.
Trial registration number
NCT03311789
Hyperthermia is a rapidly growing field in cancer therapy and many advances have been made in understanding and applying the mechanisms of hyperthermia. Secondary effects of hyperthermia have been increasingly recognized as important in therapeutic effects and multiple studies have started to elucidate their implications for treatment. Immune effects have especially been recognized as important in the efficacy of hyperthermia treatment of cancer. Both thermo‐ablative and mild hyperthermia activate the immune system, but mild hyperthermia seems to be more effective at doing so. This may suggest that mild hyperthermia has some advantages over thermo‐ablative hyperthermia and research into immune effects of mild hyperthermia should continue.
This article is categorized under:
Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease
Therapeutic Approaches and Drug Discovery > Emerging Technologies
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Background: The prognosis of patients with unresectable or metastatic biliary tract cancer (BTC) is unacceptable low. This study aimed to determine the efficacy, safety and predicting biomarkers of immune checkpoint inhibitor nivolumab in combination with chemotherapy in advanced BTCs.
Methods: In this open-label, single-arm, phase Ⅱ trial, chemo-immunology combination therapy consisting of gemcitabine 1000mg/m², cisplatin 75mg/m² plus nivolumab 3mg/kg was administered every 3 weeks for up to 6 cycles. Maintenance treatment with gemcitabine plus nivolumab was administered to patients achieving disease control following the combination therapy. The primary outcome was objective response rate (ORR). Secondary outcomes included safety, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). The exploratory objectives were to assess biomarkers for predicting clinical response and prognosis.
Results: 32 patients with a median age of 60 (range 27-69) years were enrolled. As of September 31, 2019, the median follow-up was 12.8 (95% CI, 10.8-14.8) months. 27 response-evaluable patients received a median of 4 (IQR, 3-6) cycles combination therapy, of which 15 (55.6%) patients achieved objective response, including 5 (18.6%)with complete response (CR), and the DCR was 92.6%. 2 of 6 patients in cohort A who were refractory to gemcitabine or cisplatin-based chemotherapy achieved 1 CR and 1 partial response. 13 of 21 chemotherapy-naive patients (61.9%) in cohort B achieved objective response. The median PFS of all patients in cohort A+B was 6.1 months. The median OS was 8.5 months with 33.3% 12-month OS rate. The most frequent grade 3 or higher adverse events were thrombocytopenia (56%), and neutropenia (22%). Fitness might be a biomarker for predicting clinical response. On-therapy change of serum sFASL, MCP-1 and IFN-γ were correlated with prognosis.
Conclusions: Nivolumab in combination with gemcitabine and cisplatin offer promising efficacy and manageable safety profile for patients with advanced BTCs.
Immunotherapy has recently become widely used in lung cancer. Many oncologists are focused on cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death ligand-1 (PD-L1), and programmed cell death-1 (PD-1). Immunotherapy targeting the PD-1/PD-L1 checkpoints has shown promising efficacy in non-small cell lung cancer (NSCLC), but questions remain to be answered. Among them is whether the simultaneous inhibition of other checkpoints could improve outcomes. Lymphocyte-activation gene-3 (LAG-3) is another vital checkpoint that may have a synergistic interaction with PD-1/PD-L1. Here we review the LAG-3 function in cancer, clinical trials with agents targeting LAG-3, and the correlation of LAG-3 with other checkpoints. This article is protected by copyright. All rights reserved.
Tumor cells commonly express several antigens, such as tumor-associated antigens (TAAs) or mutation-derived antigens (neoantigens),
that can be regarded as foreign antigens and elicit anti-tumor immune responses in cancer patients. Various TAAs or neoantigens
expressed in cancer cells have been identified and utilized as targets for cancer vaccines. One approach to elicit tumor-specific
immune responses is termed peptide-based cancer vaccination; it involves administrating TAAs or neoantigen-derived peptide
for treatment of cancers. There have been several forms of peptide-based cancer vaccines depending on which effector cells,
such as cytotoxic T lymphocytes (CTLs) or CD4+ T-helper cells, are targeted to be activated. Many phase I and II clinical trials of peptide-based cancer vaccines using
TAA-derived CTL epitopes, T-helper cell epitopes, or dendritic cells loaded with TAA-derived peptides for various malignant
tumors have been conducted and provide clinical benefits in a small fraction of patients. Nowadays, to improve the efficiency
of peptide-based cancer vaccines, combination immunotherapy of peptide-based cancer vaccines with the immune-checkpoint blockade
therapies using monoclonal antibodies (mAbs) specific for CTL antigen 4 (CTLA-4), programmed cell death 1 (PD-1), or PD-1
ligand 1 (PD-L1) have been developed for clinical application. Furthermore, along with the recent technological progress in
genetic and bioinformatic analysis, it has become easier to identify neoantigens from individual cancer patients. It is expected
that peptide-based cancer vaccines targeting neoantigens as a personalized cancer immunotherapy will be developed.
These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.
The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.
The most exciting recent advance for achieving durable management of advanced human cancers is immunotherapy, especially the concept of immune checkpoint blockade. However, with the exception of melanoma, most patients do not respond to immunotherapy alone. A growing body of work has shown that epigenetic drugs, specifically DNA methyltransferase inhibitors, can upregulate immune signaling in epithelial cancer cells through demethylation of endogenous retroviruses and cancer testis antigens. These demethylating agents may induce T-cell attraction and enhance immune checkpoint inhibitor efficacy in mouse models. Current clinical trials are testing this combination therapy as a potent new cancer management strategy. Cancer Res; 76(7); 1-7. ©2016 AACR.
Cancer treatments have been transformed with recent advances in cancer immunotherapy(1) . As monotherapies, these agents have demonstrated clinical activity across many tumor types. Further advances in the effectiveness of cancer immunotherapies will require targeting antitumor immune response at multiple levels, which may be accomplished through combination approaches. This review discusses the current landscape of cancer immunotherapy, combinations in clinical development, strategies for dose selection and trial design, and clinical pharmacology and regulatory considerations. This article is protected by copyright. All rights reserved.
Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies, such as dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments, and heat shock) and five potent inducers of immunogenic cell death [radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses, and (hypericin-based) photodynamic therapy] on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings.
Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens.
Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated antitumor effect can be achieved in the absence of graft-vs.-host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer, such as the failure of infused NK cells to expand and persist in vivo. Therefore, efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors, and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells; with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next few years.
Background:
Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, was associated with encouraging overall survival in uncontrolled studies involving previously treated patients with advanced renal-cell carcinoma. This randomized, open-label, phase 3 study compared nivolumab with everolimus in patients with renal-cell carcinoma who had received previous treatment.
Methods:
A total of 821 patients with advanced clear-cell renal-cell carcinoma for which they had received previous treatment with one or two regimens of antiangiogenic therapy were randomly assigned (in a 1:1 ratio) to receive 3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks or a 10-mg everolimus tablet orally once daily. The primary end point was overall survival. The secondary end points included the objective response rate and safety.
Results:
The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) with nivolumab and 19.6 months (95% CI, 17.6 to 23.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148). The objective response rate was greater with nivolumab than with everolimus (25% vs. 5%; odds ratio, 5.98 [95% CI, 3.68 to 9.72]; P<0.001). The median progression-free survival was 4.6 months (95% CI, 3.7 to 5.4) with nivolumab and 4.4 months (95% CI, 3.7 to 5.5) with everolimus (hazard ratio, 0.88; 95% CI, 0.75 to 1.03; P=0.11). Grade 3 or 4 treatment-related adverse events occurred in 19% of the patients receiving nivolumab and in 37% of the patients receiving everolimus; the most common event with nivolumab was fatigue (in 2% of the patients), and the most common event with everolimus was anemia (in 8%).
Conclusions:
Among patients with previously treated advanced renal-cell carcinoma, overall survival was longer and fewer grade 3 or 4 adverse events occurred with nivolumab than with everolimus. (Funded by Bristol-Myers Squibb; CheckMate 025 ClinicalTrials.gov number, NCT01668784.).
Oncolytic viruses represent a new class of therapeutic agents that promote anti-tumour responses through a dual mechanism of action that is dependent on selective tumour cell killing and the induction of systemic anti-tumour immunity. The molecular and cellular mechanisms of action are not fully elucidated but are likely to depend on viral replication within transformed cells, induction of primary cell death, interaction with tumour cell antiviral elements and initiation of innate and adaptive anti-tumour immunity. A variety of native and genetically modified viruses have been developed as oncolytic agents, and the approval of the first oncolytic virus by the US Food and Drug Administration (FDA) is anticipated in the near future. This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncolytic viruses in advanced clinical trials and discusses the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.
Recent advances with immunotherapy agents for the treatment of cancer has provided remarkable, and in some cases, curative results. Our laboratory has identified CD47 as an important "don't eat me" signal expressed on malignant cells. Blockade of the CD47:SIRPα axis between tumor cells and innate immune cells (monocytes, macrophages, and dendritic cells) increases tumor cell phagocytosis in both solid tumors (including, but not limited to bladder, breast, colon, lung, pancreatic) and hematological malignancies. These phagocytic innate cells are also professional antigen presenting cells (APCs), providing a link from innate to adaptive anti-tumor immunity. Preliminary studies have demonstrated that APCs present antigens from phagocytosed tumor cells, causing T cell activation. Therefore, agents that block CD47:SIRP-α engagement are attractive therapeutic targets as a monotherapy or in combination with additional immune modulating agents for activating anti-tumor T cells in vivo.
Copyright © 2015, American Association for Cancer Research.
Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial.
Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate.
Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred.
T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.
© 2015 by American Society of Clinical Oncology.
Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-kB (nuclear factor kB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligandswere formulatedwith granulocyte-macrophage colony-stimulating factor (GMCSF)-producing cellular cancer vaccines-termed STINGVAX-that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including onewith an Rp,Rp dithio diastereomer and noncanonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge zstructure, enhanced antitumor efficacy of STINGVAXinmultiple aggressive therapeuticmodels of established cancer inmice.Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8+ T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmeddeathligand1)up-regulation, which was associatedwith tumor-infiltrating CD8+IFNγ+ T cells.When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.
Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.
PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor–mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon γ, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.
Tumors constitute highly suppressive microenvironments in which infiltrating T cells are ''exhausted'' by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits anti-tumor and other CD8 + T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblock-ade of TIGIT and PD-L1 synergistically and specifically enhanced CD8 + T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's comple-mentary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8 + T cell-dependent responses.
There have been no major advances for the treatment of metastatic urothelial bladder cancer (UBC) in the last 30 years. Chemotherapy is still the standard of care. Patient outcomes, especially for those in whom chemotherapy is not effective or is poorly tolerated, remain poor. One hallmark of UBC is the presence of high rates of somatic mutations. These alterations may enhance the ability of the host immune system to recognize tumour cells as foreign owing to an increased number of antigens. However, these cancers may also elude immune surveillance and eradication through the expression of programmed death-ligand 1 (PD-L1; also called CD274 or B7-H1) in the tumour microenvironment. Therefore, we examined the anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, for the treatment of metastatic UBC. MPDL3280A is a high-affinity engineered human anti-PD-L1 monoclonal immunoglobulin-G1 antibody that inhibits the interaction of PD-L1 with PD-1 (PDCD1) and B7.1 (CD80). Because PD-L1 is expressed on activated T cells, MPDL3280A was engineered with a modification in the Fc domain that eliminates antibody-dependent cellular cytotoxicity at clinically relevant doses to prevent the depletion of T cells expressing PD-L1. Here we show that MPDL3280A has noteworthy activity in metastatic UBC. Responses were often rapid, with many occurring at the time of the first response assessment (6 weeks) and nearly all were ongoing at the data cutoff. This phase I expansion study, with an adaptive design that allowed for biomarker-positive enriched cohorts, demonstrated that tumours expressing PD-L1-positive tumour-infiltrating immune cells had particularly high response rates. Moreover, owing to the favourable toxicity profile, including a lack of renal toxicity, patients with UBC, who are often older and have a higher incidence of renal impairment, may be better able to tolerate MPDL3280A versus chemotherapy. These results suggest that MPDL3280A may have an important role in treating UBC-the drug received breakthrough designation status by the US Food and Drug Administration (FDA) in June 2014.
To prove clinical benefits of cancer vaccine is currently difficult, except for one phase III trial has documented improved overall survival with the vaccine, Sipuleucel-T, although induction of anti-tumor immune responses through cancer vaccine is theoretically promising and would be straightforward. In contrast, immune checkpoint blockade with anti-CTLA4 mAb and anti-PD-1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multiple cancer types. In addition, there is a promising novel cancer immunotherapy, CAR therapy-a personalized treatment that involves genetically modifying a patient's T-cells to make them target tumor cells. We are now facing new era of cancer immunotherapy.
Recent clinical data have emphatically shown the capacity of our immune systems to eradicate even advanced cancers. Although oncolytic viruses (OVs) were originally designed to function as tumour-lysing therapeutics, they have now been clinically shown to initiate systemic antitumour immune responses. Cell signalling pathways that are activated and promote the growth of tumour cells also favour the growth and replication of viruses within the cancer. The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses. Coupling of OV therapy with tumour antigen vaccination, immune checkpoint inhibitors and adoptive cell therapy seems to be ready to converge towards a new generation of multimodal therapeutics to improve outcomes for cancer patients.
The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy.
V-domain Ig suppressor of T cell activation (VISTA) is a potent negative regulator of T-cell function that is expressed on hematopoietic cells. VISTA levels are heightened within the tumor microenvironment, in which its blockade can enhance antitumor immune responses in mice. In humans, blockade of the related programmed cell death 1 (PD-1) pathway has shown great potential in clinical immunotherapy trials. Here, we report the structure of human VISTA and examine its function in lymphocyte negative regulation in cancer. VISTA is expressed predominantly within the hematopoietic compartment with highest expression within the myeloid lineage. VISTA-Ig suppressed proliferation of T cells but not B cells and blunted the production of T-cell cytokines and activation markers. Our results establish VISTA as a negative checkpoint regulator that suppresses T-cell activation, induces Foxp3 expression, and is highly expressed within the tumor microenvironment. By analogy to PD-1 and PD-L1 blockade, VISTA blockade may offer an immunotherapeutic strategy for human cancer. Cancer Res; 74(7); 1924-32. ©2013 AACR.
Natural killer (NK) cells are critical innate immune lymphocytes capable of destroying virally infected or cancerous cells through targeted cytotoxicity and further assisting in the immune response by releasing inflammatory cytokines. NK cells are thought to contribute to the process of tumor killing by certain therapeutic monoclonal antibodies (mAb) by directing antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIA (CD16). Numerous therapeutic mAb have been developed that target distinct cancer-specific cell markers and may direct NK cell-mediated ADCC. Recent therapeutic approaches have combined some of these cancer-specific mAb with additional strategies to optimize NK cell cytotoxicity. These include agonistic mAb targeting NK cell activating receptors and mAbs blocking NK cell inhibitory receptors to enhance NK cell functions. Furthermore, several drugs that can potentiate NK cell cytotoxicity through other mechanisms are being used in combination with therapeutic mAb. In this review, we examine the mechanisms employed by several promising agents used in combination therapies that enhance natural or Ab-dependent cytotoxicity of cancer cells by NK cells, with a focus on treatments for leukemia and multiple myeloma.
OX40 is a potent co-stimulatory receptor that can potentiate T cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function and survival of T cells. Preclinical studies have shown that OX40 agonists increase anti-tumor immunity and improve tumor-free survival. In this study, we performed a Phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12/30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4+ FoxP3+ regulatory T cells in tumor-infiltrating lymphocytes andincreased the anti-tumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in cancer patients, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells and intratumoral regulatory T cells.
These are exciting times for the field of cancer immunotherapy. Although the clinical efficacy of monoclonal antibodies has been demonstrated since the early 1990s, the therapeutic profile of other immunotherapeutic approaches-especially vaccines-has not yet been formally clarified. However, the recent success of several immunotherapeutic regimens in cancer patients has boosted the development of this treatment modality. These achievements stemmed from recent scientific advances demonstrating the tolerogenic nature of cancer and the fundamental role of the tumor immune microenvironment in the suppression of antitumor immunity. New immunotherapeutic strategies against cancer attempt to promote protective antitumor immunity while disrupting the immunoregulatory circuits that contribute to tumor tolerance. Cancer vaccines differ from other anticancer immunotherapeutics in that they initiate the dynamic process of activating the immune system so as to successfully re-establish a state of equilibrium between tumor cells and the host. This article reviews recent clinical trials involving several different cancer vaccines and describes some of the most promising immunotherapeutic approaches that harness antitumor T-cell responses. In addition, we describe strategies whereby cancer vaccines can be exploited in combination with other therapeutic approach to overcome-in a synergistic fashion-tumor immunoevasion. Finally, we discuss prospects for the future development of broad spectrum prophylactic anticancer vaccines.
A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13R alpha 2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13R alpha 2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362.)
We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×10¹¹ HLA-C∗08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C∗08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C∗08:02.
Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.
Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality.
Immunotherapy has received the expectation that it should contribute to the therapy of cancer patients for >100 years. At
long last, recent clinical trials of immunotherapy with immune checkpoint inhibitors and adoptive cell therapy with genetically
engineered T cells have reported their remarkable efficacies. Nowadays, it is expected that T-cell adoptive immunotherapy
can not only control tumor progression but even cure cancer in some patients. Conversely, severe adverse events associated
with efficacy have frequently been reported in clinical trials, suggesting that the assessment and control of safety will
be indispensable in the future development of the therapy. New approaches in T-cell adoptive immunotherapy such as reduction
of adverse events, targeting of new antigens or utilization of allogeneic cells will open a new gate for less harmful and
more effective immunological treatment of cancer patients.
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
Immunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell-derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing the immune system to treat cancer. (C) 2016 AACR.
These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.
In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.
Background:
Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.
Methods:
For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652.
Findings:
Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.
Interpretation:
Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.
Funding:
F Hoffmann-La Roche Ltd.
The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications-not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.
Significance:
Recent success obtained with adoptive transfer of CAR T cells targeting CD19 in patients with refractory hematologic malignancies has generated much enthusiasm for T-cell engineering and raises the prospect of implementing similar strategies for solid tumors. Mesothelin is expressed in a wide range and a high percentage of solid tumors, which we review here in detail. Mesothelin CAR therapy has the potential to treat multiple solid malignancies. Cancer Discov; 6(2); 1-15. ©2015 AACR.
Using the immune system to control cancer has been investigated for over a century. Yet it is only over the last several years that therapeutic agents acting directly on the immune system have demonstrated improved overall survival for cancer patients in phase III clinical trials. Furthermore, it appears that some patients treated with such agents have been cured of metastatic cancer. This has led to increased interest and acceleration in the rate of progress in cancer immunotherapy. Most of the current immunotherapeutic success in cancer treatment is based on the use of immune-modulating antibodies targeting critical checkpoints (CTLA-4 and PD-1/PD-L1). Several other immune-modulating molecules targeting inhibitory or stimulatory pathways are being developed. The combined use of these medicines is the subject of intense investigation and holds important promise. Combination regimens include those that incorporate targeted therapies that act on growth signaling pathways, as well as standard chemotherapy and radiation therapy. In fact, these standard therapies have intrinsic immune-modulating properties that can support antitumor immunity. In the years ahead, adoptive T-cell therapy will also be an important part of treatment for some cancer patients. Other areas which are regaining interest are the use of oncolytic viruses that immunize patients against their own tumors and the use of vaccines against tumor antigens. Immunotherapy has demonstrated unprecedented durability in controlling multiple types of cancer and we expect its use to continue expanding rapidly.
© 2015 Elsevier Inc. All rights reserved.
Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients.
Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma.
We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients.
Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy.
These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma.
Merck Sharp & Dohme.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature
of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent
technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise
as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor
in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer
immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell
reactivity against this class of antigens.
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
Background:
The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma.
Methods:
In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival.
Results:
The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P=0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P=0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%).
Conclusions:
The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).
Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.
Copyright © 2015 Elsevier Inc. All rights reserved.
Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma.
In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746.
Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred.
Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.
Bristol-Myers Squibb.
Copyright © 2015 Elsevier Ltd. All rights reserved.
To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies.
The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706). We also conducted a secondary analysis of OS data (n = 4,846) with an additional 2,985 patients from an expanded access program. OS rates were estimated using the Kaplan-Meier method.
Among 1,861 patients, median OS was 11.4 months (95% CI, 10.7 to 12.1 months), which included 254 patients with at least 3 years of survival follow-up. The survival curve began to plateau around year 3, with follow-up of up to 10 years. Three-year survival rates were 22%, 26%, and 20% for all patients, treatment-naive patients, and previously treated patients, respectively. Including data from the expanded access program, median OS was 9.5 months (95% CI, 9.0 to 10.0 months), with a plateau at 21% in the survival curve beginning around year 3.
To our knowledge, this is the largest analysis of OS to date for ipilimumab-treated patients with advanced melanoma. We observed a plateau in the survival curve, beginning at approximately 3 years, which was independent of prior therapy or ipilimumab dose. These data add to the evidence supporting the durability of long-term survival in ipilimumab-treated patients with advanced melanoma.
© 2015 by American Society of Clinical Oncology.
WNT-β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.
Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy.
We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614.
From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group.
Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation.
Bristol-Myers Squibb.
Generating an anti-tumor immune response is a multi-step process that is executed by effector T cells that can recognize and kill tumor targets. However, tumors employ multiple strategies to attenuate the effectiveness of T-cell-mediated attack. They achieve this by interfering with nearly every step required for effective immunity, from deregulation of antigen-presenting cells to establishment of a physical barrier at the vasculature that prevents homing of effector tumor-rejecting cells and the suppression of effector lymphocytes through the recruitment and activation of immunosuppressive cells such as myeloid-derived suppressor cells, tolerogenic monocytes, and T regulatory cells. Here, we review the ways in which tumors exert immune suppression and highlight the new therapies that seek to reverse this phenomenon and promote anti-tumor immunity. Understanding anti-tumor immunity, and how it becomes disabled by tumors, will ultimately lead to improved immune therapies and prolonged survival of patients.