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Immune checkpoint inhibitors (ICIs) with FDA approval. The scheme shows pembrolizumab, nivolumab, and cemiplimab (the PD-1 inhibitors); durvalumab, atezolizumab, and avelumab (the PD-L1 inhibitors); and ipilimumab (the CTLA-4 inhibitor). These antibodies are currently the most important ICI treatment options for a number of cancer types (image created with Biorender.com).
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Simple Summary: In recent years, checkpoint inhibitor treatment of tumors has caused a stir. The response of patients with metastases showed outstanding success for some cancer types. However, many tumor types develop resistance strategies to evade this therapeutic application. This review provides an overview of the potential and broader treatment...
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... its effectiveness in the treatment of patients with R/M HNSCC has not yet been demonstrated [92]. Figure 2 shows an overview of the currently most important approved antibodies in the field of immune chekpoint inhibition. 1 inhibitors); durvalumab, atezolizumab, and avelumab (the PD-L1 inhibitors); and ipilimumab (the CTLA-4 inhibitor). These antibodies are currently the most important ICI treatment options for a number of cancer types (image created with Biorender.com). ...
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In recent years, studies in cancer immunotherapy have focused on finding predictive response biomarkers to anticipate which patients will respond to each kind of treatment, optimizing treatment strategy and reducing toxicities and costs. Unfortunately, these studies are still limited, and no conclusive results have been obtained. Thi...
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... Immune checkpoint inhibitors (ICIs) inhibit cancer growth and metastasis by blocking the immune escape of cancer cells [6]. ICIs have revolutionized the treatment of head and neck cancer and currently play a central role against R/M HNSCC [7]. In a phase III trial for platinum-refractory R/M HNSCC (CheckMate-141), nivolumab extended overall survival (OS) compared to conventional chemotherapy [8]. ...
Background: Nivolumab has been shown to improve the overall survival (OS) of patients with recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, there is a need to identify factors associated with long-term survival (beyond 2 years) in these patients. This study investigated the relationship between pretreatment factors and long-term survival in patients with R/M HNSCC treated with nivolumab. Methods: Forty-nine patients with R/M HNSCC who were treated with nivolumab were retrospectively reviewed. Baseline characteristics, clinical data, and survival outcomes were evaluated. Univariate and multivariate analyses were performed to identify factors associated with long-term survival (OS ≥ 2 years). Results: The median OS in the overall cohort was 11.0 months, and the 2-year survival rate was 34.7%. Long-term survivors (OS ≥ 2 years) had significantly higher proportions of patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of 0 or 1, serum albumin levels ≥ 3.5 g/dL, and neutrophil-to-eosinophil ratio (NER) < 32.0 compared to non-long-term survivors. On multivariate analysis, serum albumin levels ≥ 3.5 g/dL, in addition to ECOG-PS score of 0 or 1, were independent predictors of long-term survival. Conclusions: Pretreatment serum albumin levels may be useful for predicting long-term survival in R/M HNSCC patients treated with nivolumab.
... The cost of candidate assets is reduced as poor-performing assets exit the pipeline early and patients who are unlikely to benefit from systemic dosing of a drug-and could potentially endure significant toxicity-are not included in development trials. There is significant research ongoing in the development of new immunotherapies, targeted therapeutics, and combinatorial strategies in all three of these indications (Lulla and Heslop, 2016;Banks and D'Angelo, 2022;Ettl et al., 2022), and the CIVO platform is currently being used in both HNSCC and STS to evaluate novel immunomodulating agents and/or novel combinatorial strategies. Ultimately, this drug development model is one that has the potential to help achieve the societal goal of delivering the right drug to the right patient. ...
Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit).
Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4–96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure.
Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment.
Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.
... Moreover, PD-1/PD-L1 therapy currently is only approved for patients in advanced stages of recurrent and metastatic HNC. Predicting efficacy of antibody-based immunotherapy would be highly relevant for patients [26]. ...
The programmed cell death 1 ligand 1 (PD‐L1)/programmed cell death protein 1 (PD‐1) axis is primarily associated with immunosuppression in cytotoxic T lymphocytes (CTLs). However, mounting evidence is supporting the thesis that PD‐L1 not only functions as a ligand but mediates additional cellular functions in tumor cells. Moreover, it has been demonstrated that PD‐L1 is not exclusively localized at the cellular membrane. Subcellular fractionation revealed the presence of PD‐L1 in various cellular compartments of six well‐characterized head and neck cancer (HNC) cell lines, including the nucleus. Via western blotting, we detected PD‐L1 in its well‐known glycosylated/deglycosylated state at 40–55 kDa. In addition, we detected previously unknown PD‐L1 variants with a molecular weight at approximately 70 kDa and >150 kDa exclusively in nuclear protein fractions. These in vitro findings were confirmed with primary tumor samples from head and neck squamous cell carcinoma (HNSCC) patients. Furthermore, we demonstrated that nuclear PD‐L1 variant expression is cell cycle dependent. Immunofluorescence staining of PD‐L1 in different cell cycle phases of synchronized HNC cells supported these observations. Mechanisms of nuclear PD‐L1 trafficking remain less understood; however, proximity ligation assays showed a cell‐cycle‐dependent interaction of the cytoskeletal protein vimentin with PD‐L1, whereas vimentin could serve as a potential shuttle for nuclear PD‐L1 transportation. Mass spectrometry after PD‐L1 co‐immunoprecipitation, followed by gene ontology analysis, indicated interaction of nuclear PD‐L1 with proteins involved in DNA remodeling and messenger RNA (mRNA) splicing. Our results in HNC cells suggest a highly complex regulation of PD‐L1 and multiple tumor cell‐intrinsic functions, independent of immune regulation. These observations bear significant implications for the therapeutic efficacy of immune checkpoint inhibition.
... TICs are also strongly associated with the expression of most immune checkpoints in HNSCC [10] and could potentially impact the response to immunotherapy. As a well-known tumor type with a strong immune infiltration response [11], immune-related signatures were used to predict the prognosis, immune checkpoint expression, TIC levels, and various response states after ICI treatment in HNSCC [12,13]. Immune-related signatures were more accurate in predicting OS than prediction models based on glycosyltransferase and fatty acid metabolism-related signatures [10,14]. ...
Tumor-infiltrating immune cells (TICs) affect tumorigenesis and tumor development in head and neck squamous cell carcinoma (HNSCC). We constructed a novel predictive model for HNSCC based on immune-related genes (IRGs) from The Cancer Genome Atlas and the Immunology Database and Analysis Portal. After identifying the IRGs, a predictive model involving 13 IRGs with high stratification value of overall survival (OS) was constructed by multiple support vector machine recursive feature elimination and least absolute shrinkage and selection operator regression. We explored the relationship between the risk score (RS) and clinical characteristics. The nomogram showed high concordance and good agreement in OS. Four TICs affected the OS and were in agreement with the abundance analysis of the RS levels. Furthermore, the low-risk HNSCC group showed higher expression of PD-1, CTLA4, and TIGIT, while the high-risk group showed higher expression of EGFR. The high-risk HNSCC showed high sensitivity to eight drugs.
... The use of inhibitors that block the interaction of PD-L1 with the PD-1 receptor may thus prevent the cancer from evading the immune system. As such, several PD-1 and PD-L1 inhibitors are currently being tested in the clinic for use in a wide variety of cancers, including HNSCC [383]. [384]. ...
... Anti-PD-1/PD-L1 ICIs block suppressive signalling through the PD-1/PD-L1 pathway, thus enhancing immune cell activity [432]. The increase in T cell anti-tumour action and efficacy is intended to enhance the response to tumour neoantigens and to convert HNSCC, generally known as "cold tumours" with low local immune activity, to "hot tumours" with higher local immune response [383,433]. The approved immune checkpoint inhibitors so far are the PD-1/PD-L1 blocking antibodies (e.g., pembrolizumab, an IgG4 monoclonal antibody (mAb), Keytruda, Merck and nivolumab, Opdivo, Bristol-Meyers Squibb-anti-PD-1, or avelumab and atezolizumab, duralumab-anti-PD-L1, all the IgG1 mAbs) and the blockade of CTLA-4 signalling using the CTLA-4 antibody (e.g., ipilimumab, an IgG1k mAb, tremelimumab, an IgG2 mAb) [434]. ...
... Since 2016, for patients with head and neck cancer, the U.S. Food and Drug Administration (FDA) has approved both nivolumab and pembrolizumab for resistant R/M HNSCC tumours that have not responded to platinum-based therapy. Subsequently, in 2017, the European Commission approved nivolumab for the treatment of the same patient population with HNSCC, followed shortly thereafter by pembrolizumab as monotherapy in recurrent or metastatic PD-L1-expressing HNSCCs with a tumour proportion score of ≥50% and in cases where progression occurred during or after platinum-containing chemotherapy [292,383,435]. ...
Simple Summary
According to the latest GLOBOCAN data, head and neck squamous cell carcinoma (HNSCC) represents the sixth most prevalent human malignancy. Recent studies indicate that various immune cell populations may determine the pathogenesis of HNSCCs. The aim of this review was to provide a comprehensive overview of the role of the immune response in HNSCC tumorigenesis, molecular signatures and the mechanisms regulating pro- and anti-cancer activity; it also examines their impact on the current status and future prospects of immunotherapeutic strategies for overcoming immune escape of HNSCC. The study corpus encompasses a wide range of recent molecular, observational and intervention studies on the role of immune signalling pathways and interaction between neoplastic cells and immune cells in human HNSCCs. Rapid advances in the field of immuno-oncology and the constantly growing body of knowledge concerning immunosuppressive mechanisms have allowed effective and personalized immunotherapy to be used as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. A greater understanding of the immune response in cancers may also contribute to the further identification of new potential immunological biomarkers necessary for greater clinical benefit in HNSCC patients.
Abstract
Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40–60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4⁺CD25⁺Foxp3⁺Tregs), cytotoxic CD3⁺CD8⁺ T cells (CTLs) and CD3⁺CD4⁺ T helper type 1/2/9/17 (Th1/Th2/Th9/Th17) lymphocytes, T follicular helper cells (Tfh) and CD56dim/CD16bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV+ve (HPV⁺) and HPV−ve (HPV⁻) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology.
... In addition to patients with R/M HNSCC, pembrolizumab has been studied as a monotherapy in patients with metastatic melanoma and NSCLC [211], advanced or metastatic urothelial carcinoma [212], R/R cHL [213], metastatic CRC, ESCC [214], cervical cancer, Merkel cell carcinoma, endometrial carcinoma, cutaneous squamous cell carcinoma (cSCC), and primary mediastinal large B-cell lymphoma. Cemiplimab has been approved for the treatment of locally advanced (la) or metastatic (m) cutaneous squamous cell carcinoma (cSCC) [215], basal carcinoma (BCC), and locally advanced or metastatic NSCLC [216]. However, its effectiveness in the treatment of patients with R/M HNSCC has not yet been demonstrated [217]. ...
Immunotherapy is an additional pillar when combined with traditional standards of care such as chemotherapy, radiotherapy, and surgery for cancer patients. It has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapies, including adoptive cellular therapy (ACT) and checkpoint inhibitors (CPIs), can induce durable clinical responses. However, their efficacies vary, and only subsets of cancer patients benefit from their use. In this review, we address three goals: to provide insight into the history of these approaches, broaden our understanding of immune interventions, and discuss current and future approaches. We highlight how cancer immunotherapy has evolved and discuss how personalization of immune intervention may address present limitations. Cancer immunotherapy is considered a recent medical achievement and in 2013 was selected as the "Breakthrough of the Year" by Science. While the breadth of immunotherapeutics has been rapidly expanding, to include the use of chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitor (ICI) therapy, immunotherapy dates back over 3000 years. The expansive history of immunotherapy, and related observations, have resulted in several approved immune therapeutics beyond the recent emphasis on CAR-T and ICI therapies. In addition to other classical forms of immune intervention, including human papillomavirus (HPV), hepatitis B, and the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) tuberculosis vaccines, immunotherapies have had a broad and durable impact on cancer therapy and prevention. One classic example of immunotherapy was identified in 1976 with the use of intravesical administration of BCG in patients with bladder cancer; resulting in a 70 % eradication rate and is now standard of care. However, a greater impact from the use of immunotherapy is documented by the prevention of HPV infections that are responsible for 98 % of cervical cancer cases. In 2020, the World Health Organization (WHO) estimated that 341,831 women died from cervical cancer [1]. However, administration of a single dose of a bivalent HPV vaccine was shown to be 97.5 % effective in preventing HPV infections. These vaccines not only prevent cervical squamous cell carcinoma and adenocarcinoma, but also oropharyngeal, anal, vulvar, vaginal, and penile squamous cell carcinomas. The breadth, response and durability of these vaccines can be contrasted with CAR-T-cell therapies, which have significant barriers to their widespread use including logistics, manufacturing limitations, toxicity concerns, financial burden and lasting remissions observed in only 30 to 40 % of responding patients. Another, recent immunotherapy focus are ICIs. ICIs are a class of antibodies that can increase the immune responses against cancer cells in patients. However, ICIs are only effective against tumors with a high mutational burden and are associated with a broad spectrum of toxicities requiring interruption of administration and/or administration corticosteroids; both of which limit immune therapy. In summary, immune therapeutics have a broad impact worldwide, utilizing numerous mechanisms of action and when considered in their totality are more effective against a broader range of tumors than initially considered. These new cancer interventions have tremendous potential notability when multiple mechanisms of immune intervention are combined as well as with standard of care modalities.
... To this end, by applying CGP, the authors demonstrate that CCND1 amplification (CCND1 encodes cyclin D1 which regulates the retinoblastoma protein activity and cell-cycle progression) was strongly associated with diminished reactivity to ICI and a poor prognosis independent of TMB levels and PD-L1 expression. ICI combination therapies in Head and Neck Cancers have been comprehensively reviewed by Ettl et al. [16]. The authors provide an overview of the combination of ICIs with various conventional and novel therapeutics aiming at (i) targeting inhibitory cellular mechanisms to reinforce antitumor immunity in the TME; (ii) potentiating endogenous T-cell responses against the tumor by blocking immunosuppressive factors such as IL-10, TGFβ, VEGF, COX2, and tumor glucose or glutamine metabolism; (iii) promoting T-cell expansion, function, and survival; and (iv) facilitating tumor regression by triggering a cytotoxic T cell-response, reducing the number of myeloid-derived suppressor cells, tumorassociated macrophages, and Tregs and activating dendritic cells. ...
Immune checkpoint inhibitors (ICIs) are in the spotlight of cancer treatment by increasing the probability for long-term survival in patients with metastatic disease and by considerably prolonging progression-free survival in patients at early disease stages [...]
