Checkpoint cluster: biomarkers of response

2017 ◽  
Vol 1 (5) ◽  
pp. 501-508
Author(s):  
Sara I. Pai ◽  
Lori J. Wirth
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Phase Iii ◽  
Clinical Knowledge ◽  
Two Phase ◽  
Future Directions ◽  
Phase Iii Clinical Trials ◽  
Programmed Cell Death 1

Current clinical knowledge surrounding one of the most promising immune checkpoint pathways, namely programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2, is reviewed in the context of head and neck squamous cell carcinoma. The results of two phase III clinical trials (KEYNOTE 040 and CheckMate 141) are critically examined. The utility of predictive biomarkers of response to immune checkpoint blockade, such as PD-L1/PD-L2 protein expression, interferon-gamma gene expression signatures, and mutational and neoantigen load, is discussed. Finally, we project future directions in the immuno-oncology field by discussing other promising predictive biomarkers as well as areas where the next advances are likely to take place, such as in the implementation of immune checkpoint inhibitors earlier in the course of cancer treatment and/or in combination therapies.

scholarly journals Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yalei Zhang ◽  
Ye Li ◽  
Kun Chen ◽  
Ling Qian ◽  
Peng Wang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Tumor Resistance ◽  
Systemic Delivery ◽  
Future Directions ◽  
Immunosuppressive Tumor Microenvironment ◽  
Proinflammatory Factors

AbstractIt has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.

scholarly journals Immunology and Immune Checkpoint Inhibition in Ovarian Cancer – Current Aspects

2021 ◽  
Author(s):  
Holger Bronger
Keyword(s):  
Ovarian Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Trial Data ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Success Story ◽  
Mutational Burden

AbstractIn the last decade immunotherapies such as immune checkpoint blockade (ICB) against the PD-1/PD-L1 system have revolutionised the treatment of numerous entities. To date, ovarian cancer has benefited very little from this success story. Possible causes include a rather low mutational burden compared to other tumour types, inadequate presentation of (neo-)antigens, and increased infiltration with immunosuppressive immune cells such as regulatory T cells and tumour-associated macrophages. In the clinical trials completed to date, the response rates to PD-1/PD-L1 checkpoint inhibitors have therefore been disappointingly low as well, although isolated long-term remissions have also been observed in ovarian cancer. The task now is to find suitable predictive biomarkers as well as to identify combination partners for ICB therapy that can increase the immunogenicity of ovarian cancer or overcome immunosuppressive resistance mechanisms. This paper provides an overview of the immune milieu in ovarian cancer, its impact on the effect of ICB, and summarises the clinical trial data available to date on ICB in ovarian cancer.

Therapeutic checkpoint targets: Evaluation of co-expression profiles in individual tumor and immune cells in the tumor microenvironment of FFPE tissue.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 176-176
Author(s):  
Annelies Laeremans ◽  
Na Li ◽  
Jeff Kim ◽  
Xiao-Jun Ma ◽  
Emily Park
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Expression Profiles ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Durable Response

176 Background: Interactions between tumor and immune cells in the tumor microenvironment (TME) play a key role in tumor progression and treatment response with accumulating evidence indicating a crucial role for tumor infiltrating immune cells. Although infiltrating cytotoxic T lymphocytes (CTLs) have been correlated with improved clinical outcome, they are ineffective in eradicating tumors due to their inhibition by immune checkpoint molecules. Immune checkpoint inhibitors have demonstrated therapeutic efficacy and durable response for several tumor types including non-small cell lung cancer (NSCLC). However, the majority of patients are resistant or relapse after initial response. Characterizing the TME for checkpoint expression with single-cell and spatial resolution can provide critical insight into new immunotherapeutic strategies and identify new predictive biomarkers for stratifying and identifying patients most likely to benefit from immunotherapy including PD-1/PD-L1 immune checkpoint blockade. Methods: Using RNAscope in situ hybridization, we evaluated in situ co-expression profiles of therapeutic checkpoint targets at single-cell level in the TME of 56 archived NSCLC FFPE tissues. Results: Checkpoint molecules including PD1, PD-L1, PD-L2, TIM3, LAG3, CTLA-4 and GITR were visualized in a highly specific and sensitive manner in individual cells within tissue morphological context. Multiple checkpoint molecules were detected in the same immune environment, especially in highly inflamed tumors. In addition to PD-L1, tumor cell-intrinsic expression of PD1, TIM3, LAG3, and PD-L2 was observed in a subset of samples. Furthermore, co-expression of therapeutic checkpoint targets including PD1, LAG3, and TIM3 was observed in infiltrating immune cells and tumor cells. Conclusions: Single-cell co-expression profiles of checkpoint molecules could shed light on how cancer cells evade the host immune surveillance and develop resistance against checkpoint blockades. Also, they could reveal valuable insights into combinatorial therapies for checkpoint markers co-expressed by the patient’s immune cells in the TME.

scholarly journals Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 14 (5) ◽  
pp. 476
Author(s):  
Alberto Bongiovanni ◽  
Brigida Anna Maiorano ◽  
Irene Azzali ◽  
Chiara Liverani ◽  
Martine Bocchini ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Neuroendocrine Neoplasms ◽  
Phase Ii Trials

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6–15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28–56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6–5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8–21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.

scholarly journals Current and Future Perspectives of PD-1/PDL-1 Blockade in Cancer Immunotherapy

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Rangarirai Makuku ◽  
Neda Khalili ◽  
Sepideh Razi ◽  
Mahsa Keshavarz-Fathi ◽  
Nima Rezaei
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Response To Therapy ◽  
Great Success ◽  
Future Perspectives ◽  
Antitumor Effects ◽  
Autoimmune Myocarditis

Cancer immunotherapy, which reactivates weakened immune cells of cancer patients, has yielded great success in recent years. Among immunotherapeutic agents, immune checkpoint inhibitors have been of particular interest and have gained approval by the FDA for treatment of cancers. Immune checkpoint blockade through targeting programmed cell death protein-1 (PD-1) has demonstrated promising antitumor effects in cancer immunotherapy of many different solid and hematologic malignancies. However, despite promising results, a favorable response is observed only in a fraction of patients, and there is still lack of a single therapy modality with curative ability. In this paper, we review the current and future perspectives of PD-1/L1 blockade in cancer immunotherapy, with a particular focus on predictive biomarkers of response to therapy. We also discuss the adverse events associated with PD-1/L1/2 inhibitors, ranging from severe life-threatening conditions such as autoimmune myocarditis to mild and moderate reactions such as skin rashes, and explore the potential strategies for improving the efficacy of immunotherapy with PD-1/L1 checkpoint inhibitors.

scholarly journals Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response

2020 ◽  
Vol 9 (1) ◽  
pp. 286 ◽  
Author(s):  
Qingyang Xiao ◽  
André Nobre ◽  
Pilar Piñeiro ◽  
Miguel-Ángel Berciano-Guerrero ◽  
Emilio Alba ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Current Status ◽  
Immune Checkpoints ◽  
Current Response ◽  
Epigenetic Biomarkers

Checkpoint inhibitor therapy constitutes a promising cancer treatment strategy that targets the immune checkpoints to re-activate silenced T cell cytotoxicity. In recent pivotal trials, immune checkpoint blockade (ICB) demonstrated durable responses and acceptable toxicity, resulting in the regulatory approval of 8 checkpoint inhibitors to date for 15 cancer indications. However, up to ~85% of patients present with innate or acquired resistance to ICB, limiting its clinical utility. Current response biomarker candidates, including DNA mutation and neoantigen load, immune profiles, as well as programmed death-ligand 1 (PD-L1) expression, are only weak predictors of ICB response. Thus, identification of novel, more predictive biomarkers that could identify patients who would benefit from ICB constitutes one of the most important areas of immunotherapy research. Aberrant DNA methylation (5mC) and hydroxymethylation (5hmC) were discovered in multiple cancers, and dynamic changes of the epigenomic landscape have been identified during T cell differentiation and activation. While their role in cancer immunosuppression remains to be elucidated, recent evidence suggests that 5mC and 5hmC may serve as prognostic and predictive biomarkers of ICB-sensitive cancers. In this review, we describe the role of epigenetic phenomena in tumor immunoediting and other immune evasion related processes, provide a comprehensive update of the current status of ICB-response biomarkers, and highlight promising epigenomic biomarker candidates.

scholarly journals Immune Checkpoint Inhibitory Therapy in Sarcomas: Is There Light at the End of the Tunnel?

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 360
Author(s):  
Vasiliki Siozopoulou ◽  
Andreas Domen ◽  
Karen Zwaenepoel ◽  
Annelies Van Beeck ◽  
Evelien Smits ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Small Cell Lung Carcinoma ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Routine Practice ◽  
Daily Routine ◽  
Treatment Protocols ◽  
Cell Lung Carcinoma ◽  
Clinical Trial Results

Soft tissue and bone sarcomas are a very heterogeneous group of tumors with many subtypes for which diagnosis and treatment remains a very challenging task. On top of that, the treatment choices are limited, and the prognosis of aggressive sarcomas remains poor. Immune checkpoint inhibitors (ICIs) have drawn a lot of attention last years because of their promising response rates and their durable effects. ICIs are currently widely used in the daily routine practice for the treatment of a different malignancies, such as melanoma, Hodgkin lymphoma, and non-small cell lung carcinoma. Still, ICIs are not included in the standard treatment protocols of the different sarcoma types. However, a plethora of clinical trials investigates the clinical benefit of ICIs in sarcomas. There is clear need to develop predictive biomarkers to determine which sarcoma patients are most likely to benefit from immune checkpoint blockade. This review will focus on (i) the clinical trial results on the use of ICIs in different sarcoma types; and on (ii) possible biomarkers predictive for the effectiveness of these drugs in sarcomas.

scholarly journals Clinical Efficacy and Future Prospects of Immunotherapy in Lung Cancer

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1029
Author(s):  
Tomonari Kinoshita ◽  
Hideki Terai ◽  
Tomonori Yaguchi
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Future Prospects ◽  
Phase Iii Clinical Trials ◽  
Current Therapies ◽  
New Treatment ◽  
Related Mortality

The three major conventional treatments: surgery, chemotherapy, and radiation therapy, have been commonly performed for lung cancer. However, lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has recently emerged as a very effective new treatment modality, and there is now growing enthusiasm for cancer immunotherapy worldwide. However, the results of clinical studies using immunotherapy are not always favorable. Understanding the steps involved in the recognition and eradication of cancer cells by the immune system seems essential to understanding why past immunotherapies have failed and how current therapies can be optimally utilized. In addition, the combination of immunotherapies, such as cancer vaccines and immune checkpoint inhibitors, as well as the combination of these therapies with three conventional therapies, may pave the way for personalized immunotherapy. In this review, we summarize the results of immunotherapies used in phase III clinical trials, including immune checkpoint inhibitors, and discuss the future prospects of immunotherapies in lung cancer treatment.

scholarly journals Targeting the immune milieu in gastrointestinal cancers

2020 ◽  
Vol 55 (10) ◽  
pp. 909-926
Author(s):  
Fiona Turkes ◽  
Justin Mencel ◽  
Naureen Starling
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Patient Benefit ◽  
Cancer Immunity ◽  
Skin Cancers ◽  
Anti Cancer ◽  
Targeted Agent ◽  
Gi Cancers

Abstract Gastrointestinal (GI) cancers are among the most common and lethal solid tumors worldwide. Unlike in malignancies such as lung, renal and skin cancers, the activity of immunotherapeutic agents in GI cancers has, on the whole, been much less remarkable and do not apply to the majority. Furthermore, while incremental progress has been made and approvals for use of immune checkpoint inhibitors (ICIs) in specific subsets of patients with GI cancers are coming through, in a population of ‘all-comers’, it is frequently unclear as to who may benefit most due to the relative lack of reliable predictive biomarkers. For most patients with newly diagnosed advanced or metastatic GI cancer, the mainstay of treatment still involves chemotherapy and/or a targeted agent however, beyond the second-line this paradigm confers minimal patient benefit. Thus, current research efforts are concentrating on broadening the applicability of ICIs in GI cancers by combining them with agents designed to beneficially remodel the tumor microenvironment (TME) for more effective anti-cancer immunity with intention of improving patient outcomes. This review will discuss the currently approved ICIs available for the treatment of GI cancers, the strategies underway focusing on combining ICIs with agents that target the TME and touch on recent progress toward identification of predictors of sensitivity to immune checkpoint blockade in GI cancers.

scholarly journals Progress and Challenges of Predictive Biomarkers for Immune Checkpoint Blockade

2021 ◽  
Vol 11 ◽  
Author(s):  
Yanna Lei ◽  
Xiaoying Li ◽  
Qian Huang ◽  
Xiufeng Zheng ◽  
Ming Liu
Keyword(s):  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cancer Therapies ◽  
Sustained Improvement ◽  
The Past

Over the past decade, immune checkpoint blockade (ICB) therapy has revolutionized the outlook for oncology with significant and sustained improvement in the overall patient survival. Unlike traditional cancer therapies, which target the cancer cells directly, ICB acts on the immune system to enhance anti-tumoral immunity. However, the response rate is still far from satisfactory and most patients are refractory to such treatment. Unfortunately, the mechanisms underlying such heterogeneous responses between patients to ICB therapy remain unclear. In addition, escalating costs of cancer care and unnecessary immune-related adverse events also are pertinent considerations with applications of ICB. Given these issues, identifying explicit predictive biomarkers for patient selection is an urgent unmet need to increase the efficacy of ICB therapy. The markers can be classified as tumor related and non-tumor-related biomarkers. Although substantial efforts have been put into investigating various biomarkers, none of them has been found to be sufficient for effectively stratifying patients who may benefit from immunotherapy. The present write up is an attempt to review the various emerging clinically relevant biomarkers affecting the efficacy of immune checkpoint inhibitors, as well as the limitations associated with their clinical application.

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