To do or not to do: A concise update of current clinical controversies in immune checkpoint blockade

2018 ◽  
Vol 25 (3) ◽  
pp. 663-673 ◽  
Author(s):  
Clement Chung
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Cellular Interactions ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
First Line Therapy ◽  
Programmed Death ◽  
Starting Point

Although programmed death-ligand 1 is currently the best available biomarker for first-line therapy with pembrolizumab for patients with non-small cell lung cancer and is a required companion test approved by the US Food and Drug Administration, programmed death-ligand 1 testing is an option (as a complementary test) for patients treated with nivolumab, atezolizumab, and durvalumab. Programmed death-ligand 1 expression is continuously variable and dynamic in the tumor microenvironment. Due to the complex molecular and cellular interactions involved in immune response, a single biomarker may not be sufficient to predict response to cancer immunotherapy. Integration of multiple tumor, immune response, and genomic parameters is likely to influence the future interpretation of biomarker-based treatment outcomes. This article, in a case-based format, concisely summarizes most up-to-date evidence in answering some commonly seen clinical controversies of cancer immunotherapy, in terms of (i) the predictive value of programmed death-ligand 1 as a biomarker; (ii) whether the use of steroids with checkpoint inhibitors will decrease efficacy of the latter; (iii) selection of patients for cancer immunotherapy based on immune-based response criteria, and (iv) whether the use of influenza vaccine with checkpoint inhibitors is considered safe. Until more robust, long-term prospective clinical data are available, these discussions may serve as a starting point for pharmacists to gain timely and effective management of these realistic issues.

scholarly journals Programmed Death Ligand-1 Immunohistochemistry— A New Challenge for Pathologists: A Perspective From Members of the Pulmonary Pathology Society

2016 ◽  
Vol 140 (4) ◽  
pp. 341-344 ◽  
Author(s):  
Lynette M. Sholl ◽  
Dara L. Aisner ◽  
Timothy Craig Allen ◽  
Mary Beth Beasley ◽  
Alain C. Borczuk ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Response ◽  
Clinical Practice ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

The binding of programmed death ligand-1 and ligand-2 (PD-L1 and PD-L2) to PD-1 blocks T-cell–mediated immune response to tumor. Antibodies that target programmed death receptor-1 (PD-1) will block the ligand-receptor interface, thereby allowing T cells to attack the tumor and increase antitumor immune response. In clinical trials, PD-1 inhibitors have been associated with an approximately 20% overall response rate in unselected patients with non–small cell lung cancer, with sustained tumor response in a subset of patients treated by these immune checkpoint inhibitors. Facing a proliferation of PD-L1 immunohistochemistry clones, staining platforms, and scoring criteria, the pathologist must decide on the feasibility of introducing a newly approved companion diagnostic assay that may require purchase not only of a specific antibody kit but of a particular staining platform. Given the likely reality that clinical practice may, in the near future, demand access to 4 different PD-L1 antibodies coupled with different immunohistochemistry platforms, laboratories will be challenged with deciding among this variety of testing methods, each with its own potential benefits. Another immediate challenge to PD-L1 testing in lung cancer patients is that of access to adequate tumor tissue, given that non–small cell lung cancer samples are often extremely limited in size. With PD-L1 testing it has become clear that the historically used US regulatory approach of one assay–one drug will not be sustainable. One evolving concept is that of complementary diagnostics, a novel regulatory pathway initiated by the US Food and Drug Administration, which is distinct from companion diagnostics in that it may present additional flexibility. Although pathologists need to face the practical reality that oncologists will be asking regularly for the PD-L1 immunohistochemistry status of their patients' tumors, we should also keep in mind that there may be room for improvement of biomarkers for immunotherapy response. The field is rich with opportunities for investigation into biomarkers of immunotherapy response, particularly in the form of collaborative, multidisciplinary studies that incorporate oncologists, pathologists, and basic scientists. Pathologists must take the lead in the rational incorporation of these biomarkers into clinical practice.

scholarly journals Is There a Role for Programmed Death Ligand-1 Testing and Immunotherapy in Colorectal Cancer With Microsatellite Instability? Part II—The Challenge of Programmed Death Ligand-1 Testing and Its Role in Microsatellite Instability-High Colorectal Cancer

2017 ◽  
Vol 142 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Esmeralda Celia Marginean ◽  
Barbara Melosky
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Microsatellite Instability ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Immune Checkpoints ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Context.— The world of oncology has changed dramatically in the past few years with the introduction of checkpoint inhibitors and immunotherapy. The promising findings of a small, phase 2 clinical trial that led to the US Food and Drug Administration breakthrough designation and approval of the anti–programmed death receptor-1 (PD-1) drug pembrolizumab (Keytruda, Merck, Kenilworth, New Jersey) to treat metastatic/refractory microsatellite instability–high colorectal cancer (CRC) has significantly boosted interest in immunomodulatory therapies in microsatellite instability–high CRC. Objectives.— To review the immune response to cancer and the role of immune checkpoints, focusing on the technical and interpretation challenges of PD-1/programmed death ligand-1 (PD-L1) testing by pathologists and the clinical implications of the test and the therapeutic potential of treating CRC with checkpoint inhibitors. Data Sources.— A PubMed review was performed of articles pertaining to CRC, microsatellite instability and mismatch repair systems, molecular classification, immune response, PD-1/PD-L1, and immunotherapy. Conclusions.— Exciting success with anti–PD-1/PD-L1 and anticytotoxic T-lymphocyte–associated protein 4 (CTLA4) checkpoint inhibitors has already been reported in melanoma and in lung and renal carcinomas. Recently, microsatellite instability–high CRCs, expressing PD-L1 by immunohistochemistry, regardless of the level of that PD-L1 expression, appeared to respond to checkpoint blockades with anti–PD-1 or anti–PD-L1 agents, whereas microsatellite-stable tumors were much less responsive. With microsatellite instability routinely tested by most centers, studies that include larger cohorts are required to study the predictive role of PD-1/PD-L1 expression in microsatellite instability–high CRC, to assess which immunohistochemistry antibodies to use, to refine the scoring criteria, and to critically analyze the interpretation pitfalls.

An innovative combined immunization platform for personalized cancer immunotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14225-e14225
Author(s):  
Jessica Matta ◽  
Célia Matta ◽  
Emilie Thiebault Peter ◽  
David Moulaert ◽  
Robert Drillien ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Vector Coding ◽  
Melanoma Model ◽  
Dna Vector ◽  
Personalized Cancer

e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.

scholarly journals Biomarkers in Immunotherapy-Based Precision Treatments of Digestive System Tumors

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhu Zeng ◽  
Biao Yang ◽  
Zhengyin Liao
Keyword(s):  
Digestive System ◽  
Checkpoint Inhibitors ◽  
Circulating Tumor Dna ◽  
Gastrointestinal Malignancies ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
Programmed Death ◽  
Potential Biomarker ◽  
Tumor Mutational Burden ◽  
Programmed Death 1

Immunotherapy, represented by immune checkpoint inhibitors (mainly referring to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockades), derives durable remission and survival benefits for multiple tumor types including digestive system tumors [gastric cancer (GC), colorectal cancer (CRC), and hepatocellular carcinoma (HCC)], particularly those with metastatic or recurrent lesions. Even so, not all patients would respond well to anti-programmed death-1/programmed death-ligand 1 agents (anti-PD-1/PD-L1) in gastrointestinal malignancies, suggesting the need for biomarkers to identify the responders and non-responders, as well as to predict the clinical outcomes. PD-L1expression has increasingly emerged as a potential biomarker when predicting the immunotherapy-based efficacy; but regrettably, PD-L1 alone is not sufficient to differentiate patients. Other molecules, such as tumor mutational burden (TMB), microsatellite instability (MSI), and circulating tumor DNA (ctDNA) as well, are involved in further explorations. Overall, there are not still no perfect or well-established biomarkers in immunotherapy for digestive system tumors at present as a result of the inherent limitations, especially for HCC. Standardizing and harmonizing the assessments of existing biomarkers, and meanwhile, switching to other novel biomarkers are presumably wise and feasible.

scholarly journals Clinical significance of checkpoint regulator “Programmed death ligand-1 (PD-L1)” expression in meningioma: review of the current status

2021 ◽  
Vol 151 (3) ◽  
pp. 443-449
Author(s):  
Shirin Karimi ◽  
Sheila Mansouri ◽  
Farshad Nassiri ◽  
Severa Bunda ◽  
Olivia Singh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tumor Heterogeneity ◽  
Checkpoint Inhibitors ◽  
Primary Brain Tumor ◽  
Current Status ◽  
High Grade ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
Programmed Death

Abstract Introduction Meningioma is the most common primary brain tumor. Most meningiomas are benign; however, a subset of these tumors can be aggressive, presenting with early or multiple tumor recurrences that are refractory to neurosurgical resection and radiotherapy. There is no standard systemic therapy for these patients, and post-surgical management of these patients is usually complicated due to lack of accurate prediction for tumor progression. Methods In this review, we summarise the crucial immunosuppressive role of checkpoint regulators, including PD-1 and PD-L1 interacting in the tumor microenvironment, which has led to efforts aimed at targeting this axis. Results Since their discovery, checkpoint inhibitors have significantly improved the outcome in many types of cancers. Currently, targeted therapy for PD-1 and PD-L1 proteins are being tested in several ongoing clinical trials for brain tumors such as glioblastoma. More recently, there have been some reports implicating increased PD-L1 expression in high-grade (WHO grades II and III) meningiomas. Several clinical trials are underway to assess the efficacy of checkpoint inhibitors in the therapeutic management of patients with aggressive meningiomas. Here, we review the immune suppressive microenvironment in meningiomas, and then focus on clinical and pathological characterization and tumor heterogeneity with respect to PD-L1 expression as well as challenges associated with the assessment of PD-L1 expression in meningioma. Conclusion We conclude with a brief review of ongoing clinical trials using checkpoint inhibitors for the treatment of high-grade and refractory meningiomas.

scholarly journals Integration of tumor inflammation, cell proliferation, and traditional biomarkers improves prediction of immunotherapy resistance and response

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sarabjot Pabla ◽  
R. J. Seager ◽  
Erik Van Roey ◽  
Shuang Gao ◽  
Carrie Hoefer ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Cell Activation ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Host Immune Response ◽  
Gene Signature ◽  
B Cell Activation ◽  
Rna Seq ◽  
Multiple Tumor

Abstract Background Contemporary to the rapidly evolving landscape of cancer immunotherapy is the equally changing understanding of immune tumor microenvironments (TMEs) which is crucial to the success of these therapies. Their reliance on a robust host immune response necessitates clinical grade measurements of immune TMEs at diagnosis. In this study, we describe a stable tumor immunogenic profile describing immune TMEs in multiple tumor types with ability to predict clinical benefit from immune checkpoint inhibitors (ICIs). Methods A tumor immunogenic signature (TIGS) was derived from targeted RNA-sequencing (RNA-seq) and gene expression analysis of 1323 clinical solid tumor cases spanning 35 histologies using unsupervised analysis. TIGS correlation with ICI response and survival was assessed in a retrospective cohort of NSCLC, melanoma and RCC tumor blocks, alone and combined with TMB, PD-L1 IHC and cell proliferation biomarkers. Results Unsupervised clustering of RNA-seq profiles uncovered a 161 gene signature where T cell and B cell activation, IFNg, chemokine, cytokine and interleukin pathways are over-represented. Mean expression of these genes produced three distinct TIGS score categories: strong (n = 384/1323; 29.02%), moderate (n = 354/1323; 26.76%), and weak (n = 585/1323; 44.22%). Strong TIGS tumors presented an improved ICI response rate of 37% (30/81); with highest response rate advantage occurring in NSCLC (ORR = 36.6%; 16/44; p = 0.051). Similarly, overall survival for strong TIGS tumors trended upward (median = 25 months; p = 0.19). Integrating the TIGS score categories with neoplastic influence quantified via cell proliferation showed highly proliferative and strong TIGS tumors correlate with significantly higher ICI ORR than poorly proliferative and weak TIGS tumors [14.28%; p = 0.0006]. Importantly, we noted that strong TIGS and highly [median = not achieved; p = 0.025] or moderately [median = 16.2 months; p = 0.025] proliferative tumors had significantly better survival compared to weak TIGS, highly proliferative tumors [median = 7.03 months]. Importantly, TIGS discriminates subpopulations of potential ICI responders that were considered negative for response by TMB and PD-L1. Conclusions TIGS is a comprehensive and informative measurement of immune TME that effectively characterizes host immune response to ICIs in multiple tumors. The results indicate that when combined with PD-L1, TMB and cell proliferation, TIGS provides greater context of both immune and neoplastic influences on the TME for implementation into clinical practice.

scholarly journals PD-L1 Targeting Immune-Microbubble Complex Enhances Therapeutic Index in Murine Colon Cancer Models

2020 ◽  
Vol 14 (1) ◽  
pp. 6
Author(s):  
Daehyun Kim ◽  
Seung Soo Lee ◽  
Hyungwon Moon ◽  
So Yeon Park ◽  
Hak Jong Lee
Keyword(s):  
Cancer Immunotherapy ◽  
Focused Ultrasound ◽  
Therapeutic Potential ◽  
Checkpoint Inhibitors ◽  
Therapeutic Index ◽  
Treatment Regimens ◽  
Cancer Models ◽  
Programmed Death ◽  
Murine Colon ◽  
Cell Death Protein

Cancer immunotherapy has revolutionized the way different neoplasms are treated. Among the different variations of cancer immunotherapy, the checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis have been validated and are currently used in the clinics. Nevertheless, these therapeutic antibodies are associated with significant side effects and are known to induce immune-related toxicities. To address these issues, we have developed an immune-microbubble complex (IMC) which not only reduces the toxicities associated with the antibodies but also enhances the therapeutic efficacy when combined with focused ultrasound. The concept of IMCs could be applied to any type of antibody-based treatment regimens to maximize their therapeutic potential.

scholarly journals Acute Tubulointerstitial Nephritis in a Patient on Anti-Programmed Death-Ligand 1 Triggered by COVID-19: A Case Report

2021 ◽  
Vol 8 ◽  
pp. 205435812110147
Author(s):  
Dimitry Buyansky ◽  
Catherine Fallaha ◽  
François Gougeon ◽  
Marie-Noëlle Pépin ◽  
Jean-François Cailhier ◽  
...  
Keyword(s):  
Case Report ◽  
Severe Acute Respiratory Syndrome ◽  
Tubulointerstitial Nephritis ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
High Dose ◽  
Programmed Death Ligand 1 ◽  
Acute Tubulointerstitial Nephritis ◽  
Programmed Death ◽  
Kidney Involvement

Rationale: Immune checkpoint inhibitors are monoclonal antibodies used in the treatment of various types of cancers. The downside of using such molecules is the potential risk of developing immune-related adverse events. Factors that trigger these autoimmune side effects are yet to be elucidated. Although any organ can potentially be affected, kidney involvement is usually rare. In this case report, we describe the first known instance of a patient being treated with an inhibitor of programmed death-ligand 1 (anti-PD-L1, a checkpoint inhibitor) who develops acute tubulointerstitial nephritis after contracting the severe acute respiratory syndrome coronavirus 2. Presenting concerns of the patient: A 62-year-old patient, on immunotherapy treatment for stage 4 squamous cell carcinoma, presents to the emergency department with symptoms of lower respiratory tract infection. Severe acute kidney injury is discovered with electrolyte imbalances requiring urgent dialysis initiation. Further testing reveals that the patient has contracted the severe acute respiratory syndrome coronavirus 2. Diagnosis: A kidney biopsy was performed and was compatible with acute tubulointerstitial nephritis. Interventions: The patient was treated with high dose corticosteroid therapy followed by progressive tapering. Outcomes: Rapid and sustained normalization of kidney function was achieved after completion of the steroid course. Novel findings: We hypothesize that the viral infection along with checkpoint inhibitor use has created a proinflammatory environment which led to a loss of self-tolerance to renal parenchyma. Viruses may play a more important role in the pathogenesis of autoimmunity in this patient population than was previously thought.

scholarly journals The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhengguo Wu ◽  
Shang Li ◽  
Xiao Zhu
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Checkpoint Inhibitors ◽  
The Body ◽  
Research Progress ◽  
Effective Population ◽  
Cell Components

Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

Sign in / Sign up

Export Citation Format

Share Document