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.

scholarly journals The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 666 ◽  
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Athanasios G. Papavassiliou ◽  
Michalis V. Karamouzis
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Epigenetic Alterations ◽  
Primary Resistance ◽  
Cellular Processes ◽  
Mutational Burden ◽  
Number Of Patients ◽  
Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

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 Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

2020 ◽  
Author(s):  
Yu Rebecca Miao ◽  
Kaushik N. Thakkar ◽  
Jin Qian ◽  
Mihalis S. Kariolis ◽  
Huang Wei ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Binding Affinity ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Multiple Cancer ◽  
Patient Response ◽  
Binding Interface

AbstractImmune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6- to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000- and 200- fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superior in vivo efficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface.One Sentence SummaryDual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with αPD-1 and αPD-L1 antibodies in ovarian cancer.

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 Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Katrin Aslan ◽  
Verena Turco ◽  
Jens Blobner ◽  
Jana K. Sonner ◽  
Anna Rita Liuzzi ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Tumor Regression ◽  
Predictive Biomarkers ◽  
Resistance Mechanisms ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Experimental Gliomas ◽  
T Cell Suppression ◽  
Response Modeling ◽  
Syngeneic Tumors

Abstract Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.

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.

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.

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