Figure - available from: Journal of Hematology & Oncology
This content is subject to copyright. Terms and conditions apply.
Source publication
Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience...
Citations
... Однако ингибирование иммунных контрольных точек может приводить к нарушению регуляции иммунного ответа и изменению активности иммунокомпетентных клеток в организме, что проявляется развитием аутоиммуноподобных реакций. Такие реакции называются иммуноопосредованными нежелательными явлениями (иоНЯ) [1][2][3]12]. Любые органы и системы организма могут поражаться на фоне терапии ингибиторами контрольных точек иммунного ответа [4][5][6][7][8][9][10]. Спектр осложнений различается в зависимости от применения анти-CTLA-4или анти-PD-1/PD-L1-моноклональных антител. ...
Checkpoint inhibitors have radically changed the approach to oncology and have become the new standard of treatment for many solid tumors, significantly increasing the life expectancy of patients. With the advent of a new class of drugs, we are faced with a completely recognized toxicity profile. The spectrum affects other manifestations that affect almost every organ and system of the body. Most often the skin, the secretion of the internal gland, the gastrointestinal tract, lungs, and liver are affected. Complications from the urinary, cardiovascular, muscular-articular, nervous and hematopoietic systems occur less frequently. This article will discuss one of the rare complications that occurs during therapy with checkpoint inhibitors — thrombocytopenia with hemorrhagic syndrome. The main purpose of the article is to increase clinical alertness and highlight the relevance of the problem of rare complications during immunotherapy.
... The observed decline in tumor markers, the immune response activation, the tumor regression documented by MRI, and the improved patient well-being collectively suggest a positive effect of BITAP immunization in combination with standard-of-cares SoCs. This finding aligns with emerging research indicating that combination strategies of chemo-and immunotherapies may yield more comprehensive and effective treatment outcomes (7,8). In a recent phase I trial of an individualized neoantigen vaccine, a tolerable and neoantigen-specific T cell response was reported in 50% of the pancreatic cancer patients. ...
This report details a case of pancreatic cancer with liver metastasis that exhibited a positive immune response to personalized immunization therapy. Our study involved the identification of neoantigens and their corresponding immunogenic peptides using an in-house bioinformatic pipeline. This process included the identification of somatic mutations through DNA/RNA sequencing of solid tumor tissue and blood liquid biopsy. Computational prediction techniques were then employed to identify novel epitopes, followed by the design and manufacture of patient-specific immunization peptides. In combination with standard-of-care chemotherapy, the patient received a sequence of 5 biweekly prime injections followed by 2 boost injections 2 and 5 months later. The peptides were emulsified in Montanide and the injection-site was conditioned with nivolumab and imiquimod. The combined regimen of peptide immunization and chemotherapy resulted in a notable decline in CA19-9 tumor marker levels following both prime and boost applications. Subsequent MRI assessments revealed a reduction in the size of liver metastases several months post-immunization initiation. Importantly, the patient showed and improved overall survival and reported an improved quality of life without experiencing significant treatment-related adverse effects. This case underscores the potential benefits of personalized peptide-based immunization as an adjunctive therapy in the treatment of advanced pancreatic cancer, showcasing promising outcomes in tumor marker reduction, tumor shrinkage, and enhanced patient well-being.
... The combination of cancer vaccines with ICBs has great potential for application, but inadequate tumor antigen presentation and immature dendritic cell development hinder vaccine efficacy. [29][30][31] FCS has been reported to interact with the model antigen ovalbumin and immune adjuvants to effectively promote dendritic cell maturation and cross-presentation. Therefore, we first investigated the ability of FCS-binding nano-formulations to mimic the ability of DC to activate and enhance antigen presentation, a fundamental requirement for initiating and modulating the innate and adaptive immune systems. ...
Intravesical instillation‐based immunotherapy for bladder‐preservation of bladder cancer (BCa) treatment has not been explored. In the current study, two irrigated nano‐formulations of immunological adjuvant‐fluorinated chitosan (FCS) and therapeutic antibody‐FCS are developed for synergistic immunotherapy against BCa. In this system, FCS is employed as a transepithelial carrier to assemble with bovine serum albumin (BSA)‐flubendazole (FBZ) complex and anti‐PD‐1 (αPD‐1) respectively, to facilitate efficient transepithelial delivery of intravesical FBZ‐BSA and αPD‐1 though transiently regulating the distribution of tight junction proteins on bladder epithelium. In addition, the FBZ–BSA complex exhibits tumor microenvironment‐responsive charge reversal and BSA carrier‐broken effects to drive tumor‐targeted dissociation and drug release of FBZ–BSA/FCS. Moreover, FBZ not only promotes apoptosis and inhibits glycolysis in cancer cells but also displays adjuvant properties to activate potent immune responses through IL‐12/IFN‐γ pathway. Interestingly, combined perfusion of FBZ–BSA/FCS and αPD‐1/FCS nano‐formulations can significantly activate the tumor immune microenvironment, especially CD8⁺ T cell infiltration and αPD‐1 sensitivity, and finally remarkably inhibit tumor growth in the mouse orthotopic BCa model. Thus, this study presents a novel intravesical delivery platform for ICB antibodies and a smart adjuvant system to achieve potent synergy immunotherapy, which is promising for bladder‐preserving treatment against BCa.
... Lenvatinib, a multi-kinase inhibitor of angiogenic (including VEGF receptor) and oncogenic receptor tyrosine kinases, can exert immunomodulatory effects via inhibiting the infiltration of immunosuppressive cells (Treg cells) and activating cytotoxic CD8 + T cells [8]. Thus, combining multiple receptor tyrosine kinase inhibitor (TKI) with immune checkpoint inhibitors (ICIs) is expected to enhance anti-cancer immunity, which has already been proved by preclinical and clinical studies [9][10][11]. Combining lenvatinib with pembrolizumab (anti-PD-1) has already demonstrated clinical efficacy in various solid tumors [12,13], including gastric cancer [14]. ...
Background
Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC.
Methods
Histologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate.
Results
Nine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07–11.27) and 13.17 months (95% CI 2.78–23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183.
Conclusions
GLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment.
... The dense extracellular matrix of tumors poses a significant challenge for CAR-T therapeutics, hindering the effective infiltration of T cells into solid tumors. Given the ability of macrophages to penetrate tumors and enlist and stimulate T cells, it is logical to simultaneously administer CAR-Ms and CAR-T cells to optimize the effectiveness against tumors [111][112][113]. In fact, when HER2-targeted CAR-Ms and polyclonal T cells from the donor were given together, they exhibited a more powerful antitumor reaction compared to each treatment individually in a metastatic SKOV3-xenograft mouse model. ...
Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.
Graphical Abstract
... However, its effectiveness in many populations still needs to be greatly improved. 3 Since the first approval of immune checkpoint inhibitors (ICIs) for unresectable malignant melanoma, several different tumor types have benefited from United States Food and Drug Administration (US FDA)-approved therapeutic indications regarding ICIs, and applications in this area are rapidly evolving. 4,5 However, the effect of immunotherapy is not effective in all populations, and according to clinical data, only about one-third of patients show good treatment response in tumor immunotherapy. ...
Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining tumor growth information and require more accurate and easy‐to‐operate tumor information detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real‐time detection tool for detecting information directly or indirectly released by tumors in human body fluids, which is more suitable for the requirements of new tumor treatment modalities. Liquid biopsy has not been widely used in clinical practice, and there are fewer reviews of related clinical applications. This review summarizes the clinical applications of liquid biopsy components (e.g., circulating tumor cells, circulating tumor DNA, extracellular vesicles, etc.) in tumorigenesis and progression. This includes the development process and detection techniques of liquid biopsies, early screening of tumors, tumor growth detection, and guiding therapeutic strategies (liquid biopsy‐based personalized medicine and prediction of treatment response). Finally, the current challenges and future directions for clinical applications of liquid biopsy are proposed. In sum, this review will inspire more researchers to use liquid biopsy technology to promote the realization of individualized therapy, improve the efficacy of tumor therapy, and provide better therapeutic options for tumor patients.
... For instance, using drug combinations that target multiple pathways can reduce the likelihood of resistance emerging. Studies have shown that combining different immunotherapies with other modalities can enhance the overall anti-cancer response [125]. Adaptive treatment strategies can also be employed in which treatment schedule adjustment, such as intermittent dosing, may help prevent or delay the onset of resistance [126,127]. ...
... Combination therapy is currently considered an optimal approach to enhance the feasibility of cancer treatment by increasing the number of antigen-presenting cells (APCs) and released tumor antigens. Multiple clinical trials have demonstrated that PD-1/PD-L1 mAbs can be a part of highly effective therapeutic combination regimens, and have evaluated their clinical efficacy alongside other inhibitors in treating malignancies 24,25 . anti-angiogenic factors in a malignant environment, thereby modifying the balance in favor of pro-angiogenic factors and activating angiogenesis. ...
Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.
... Interferon alpha-2b (IFNα2b) and IL-2 have been the only clinically approved cytokine therapeutics for cancer treatment [22]. However, with the development of technology and engineering, combination treatments of interferons and interleukins with immune checkpoint inhibitors are expected to reach success [23,24]. In this context, the use of inbacicept (IL-15 analog) in combination with the Bacillus Calmette-Guérin vaccine (BCG) significantly increased the complete response rates of patients with bladder cancer [25]. ...
Purpose of Review
This review aims to synthesize the latest advances in immunotherapeutic cancer treatment approaches and spotlight groundbreaking discoveries and clinical trial outcomes.
Recent Findings
Immunotherapy represents a promising and transformative strategy for treating a variety of hematological malignancies and solid tumors. This therapeutic approach strives to bolster the body's inherent defense mechanisms to elicit enduring, specific, and individualized anti-tumor responses by harnessing the immune system's ability to identify and eradicate cancer cells. Various modes of immunotherapy—including monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, adoptive T-cell therapies, and oncolytic viruses—have achieved considerable success in clinical trials and patient results.
Summary
Despite notable successes, challenges persist in the broader adoption of immunotherapy. Issues such as resistance mechanisms, tumor heterogeneity, and the complexity of the tumor microenvironment can weaken immune responses and constrain the efficacy of treatments. The current review is dedicated to understanding these obstacles and devising comprehensive strategies to surmount resistance and secure sustained responses.
... This highlights the need for a new strategy in the clinic for patients who experience disease progression after developing EGFR-TKI resistance. Currently, many ICI antibody monotherapies or combined therapies, such as pembrolizumab, nivolumab, and atezolizumab, have been approved by the Food and Drug Administration for clinical application in lung cancer [4][5][6]. However, immunotherapy in NSCLC patients with EGFR mutations is still controversial. ...
Background
Effective treatment after EGFR-TKI resistance is of great clinical concern. We aimed to investigate the efficacy and safety of anlotinib in combination with an anti-PD-1/PD-L1 antibody in later-line therapy for EGFR-mutant NSCLC patients after TKI treatment failure and to explore the independent predictive factors of therapeutic efficacy.
Methods
A total of 71 patients with confirmed advanced EGFR-mutated NSCLC who progressed after previous standard EGFR-TKI therapy but still failed after multiline treatments were included retrospectively in this study. Most of the patients had previously received at least three lines of treatment. All were treated with anlotinib combined with anti-PD-1 or anti-PD-L1 therapy. The safety of this combined treatment was assessed by the incidence of adverse events. The efficacy of the regimens was evaluated by survival analysis (OS, PFS, ORR, DCR).
Results
The median follow-up period was 28.6 months (range: 2.3–54.0 months), and the median number of treatment lines was 4. The overall response rate (ORR) and disease control rate (DCR) were 19.7% and 77.5%, respectively. The median PFS was 5.8 months (95% CI 4.2–7.4 months), and the median OS was 17.1 months (95% CI 12.0–22.3 months). Patients who received immune checkpoint inhibitors plus anlotinib had an encouraging intracranial ORR of 38.5% and a DCR of 80.8%. ECOG performance status < 2 at baseline was independent protective factors of PFS. Metastatic organs and ECOG performance status were independent parameters in predicting OS. Treatment-related adverse events occurred in 66 (93.0%) patients; most of the adverse events were Grade 1–2, and no increase in adverse events was observed compared to monotherapy.
Conclusion
Anlotinib combined with an anti-PD-1/PD-L1-based regimen exhibited promising efficacy and tolerance in NSCLC patients with EGFR mutations after previous TKI failure. The efficacy of this combined regimen in patients with EGFR mutations should be further evaluated.
