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.

Status of Programmed Death Ligand 1 (PD-L1) by Immunohistochemistry and Scoring Algorithms

2020 ◽  
Vol 21 (13) ◽  
pp. 1286-1292 ◽  
Author(s):  
Francesca Giunchi ◽  
Thomas Gevaert ◽  
Marina Scarpelli ◽  
Michelangelo Fiorentino
Keyword(s):  
Clinical Trials ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Scoring Systems ◽  
Companion Diagnostics ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
L1 Protein ◽  
Scoring Algorithms

The detection of the Programmed Death Ligand 1 (PD-L1) protein by immunohistochemistry is currently the only approved test predictive of response to drugs targeting the PD1/PDL1 axis. The role of this test is debated since several reagents have been used as companion diagnostics for different drugs on diverse immunostaining platforms. In addition, different scoring systems for PD-L1 immunohistochemistry have been applied in the registration studies regarding single drugs. This review deals with the various issues that are related to the immunohistochemical test for PD-L1. We discuss currently unsolved problems such as the advantages and the flaws of PD-L1 immunohistochemistry; the choice of the best reagents and the best scoring system. Finally, we review the current experiences on the role of immunohistochemistry for PD-L1 in clinical trials with immune checkpoint inhibitors.

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.

scholarly journals The Role of Checkpoint Inhibitors in Adults with Classical Hodgkin Lymphoma; A Systematic Review and Meta-Analysis of Phase II and III Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Yazan Samhouri ◽  
Muhammad Yasir Anwar ◽  
Ali Younas Khan ◽  
Urwat Til Vusqa ◽  
Iqraa Ansar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Classical Hodgkin Lymphoma ◽  
Programmed Death ◽  
Phase Ii And Iii

Introduction The ability of the neoplastic cells to escape from immune surveillance has been considered as a hallmark of cancer. The upregulation of programmed death-1 (PD-1) and programmed death ligand-1/2 (PDL-1) axis is a major immune escape pathway in multiple malignancies including classical hodgkin lymphoma (cHL). Disruption of PD1-PDL1/2 pathway using checkpoint inhibitors (CPIs) leads to reactivation of immune cells to attack malignant cells. CPIs have been studied in cHL in different settings. Here in, we did a systematic review and meta-analysis of phase II and III clinical trials that looked at the efficacy of CPIs in cHL Methods We did a comprehensive literature search, using 4 major databases (pubmed, embase, chocrane, and clinialtrials.gov). We used MeSH terms and related keywords that included all CPIs in generic and trade names, and cHL. We included phase II and III prospective clinical trials in patients > 18 year-old. We excluded case reports, case series, review articles, retrospective and observational studies, and phase I clinical trials. Initial search resulted in 1647 articles. After applying the inclusion and exclusion criteria, we had 13 articles that we explored in details. We stratified the articles according to CPIs and did a pooled-analysis of the complete response (CR) rate. Medcalc was used to do the statistical analysis. Results Of those 13 clinical trials, we had 12 phase II trials and 1 phase III trial. Nivolumab was studied in 7 trials (n=568), pembrolizumab in 5 trials (n=427), and camrelizumab in 1 trial (n=86). Table 1 shows the characteristics of these trials. (table 1) Four studies evaluated the efficacy of nivolumab in the relapsed/refractory (RR) setting. Armand et al (2018) evaluated the efficacy of nivolumab after autologous hematopoietic stem cell transplantation (auto-HSCT), the cohort in this study was divided into 3 groups: patients who received brentuximab vedotin (BV) after auto-HSCT, patients who are BV naïve, and patients who received BV before and/or after auto-HSCT. Overall response rate (ORR) and CR were 68% and 13%, 65% and 29%, 73% and 12%, respectively. Maruyama et al (2017) reported ORR and CR of 81.3% and 25%, in 16 Japanese patients received nivolumab in combination with BV. The ORR and CR in the remaining 2 trials were: 82% and 59%, and 85% and 67%. In the frontline setting, nivolumab showed ORR and CR of 84% and 67% (Ramchandren et al, 2019), 96%-100% and 53-85% (Brockelmann et al, 2019 in 2 different dosing regimens), and 100% and 72% (Yasenchack et al, 2019). Pooled analysis of all nivolumab trials showed CR rate of 47.4 % (95% CI 29.0-66.1) (figure 1) Pembrolizumab was evaluated in 4 clinical trials in the RR setting. Armand et el (2019) reported CR rate of 83% in 25 patients. Chen et al (2019) reported ORR and CR of 76.8 % and 26.1% in patients who relapsed after auto-HSCT and BV, 66.7% and 25.9% in patients ineligible for HSCT, and 73.3% and 31.7% in patients who relapsed after auto-HSCT with no prior exposure to BV. In combination with gemcitabine, vinorelbone , and doxorubicin, pembrolizumab showed ORR and CR of 100% and 93%, respectively. The only phase III clinical trial compared pembrolizumab vs BV in the RR setting showed ORR of 65.6% vs 54% and CR of 24.5% vs 24%, respectively. Only one study evaluated pembrolizumab in the frontline setting, ORR and CR of 100% in 30 patients received 3 cycles of pembolizumab followed by 4-6 cycles of doxorubicin, vinblastine, and dacarbazine. Pooled analysis of all pembrolizumab trials showed CR rate of 54.4% (95% CI 32.6-77.2) (figure 2) Only one trial evaluated the role of camrelizumab as monotherapy or in combination with decitabine. The combination regimen showed ORR and CR of 95% and 71% in CPIs naïve patients, and 52% and 28% in patients previously received CPIs. Camrelizumab monotherapy showed ORR and CR of 90% and 32% in CPIs naïve patients. Conclusion CPIs in cHL have showed high rates of response in the frontline and RR settings, with fairly acceptable toxicity profile. Their efficacy was studied post HSCT and BV, in BV naïve patients, and in HSCT-ineligible patients. Pembrolizumab and nivolumab were the 2 most studied CPIs. Future direction should focus on more studies in the frontline setting, the role of combined CPIs with other CPIs or with novel agents, to spare this relatively young population the long term toxicity of chemotherapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.Fazal:Jansen:Speakers Bureau;Jazz Pharma:Consultancy, Speakers Bureau;Stemline:Consultancy, Speakers Bureau;Glaxosmith Kline:Consultancy, Speakers Bureau;Gilead/Kite:Consultancy, Speakers Bureau;Amgen:Consultancy, Speakers Bureau;Novartis:Consultancy, Speakers Bureau;Agios:Consultancy, Speakers Bureau;BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Speakers Bureau;Karyopham:Speakers Bureau;Incyte Corporation:Consultancy, Honoraria, Speakers Bureau;Takeda:Consultancy, Speakers Bureau.

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.

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 Oncolytic Viruses for Malignant Glioma: On the Verge of Success?

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1294
Author(s):  
Yogesh R. Suryawanshi ◽  
Autumn J. Schulze
Keyword(s):  
Immune Responses ◽  
Malignant Glioma ◽  
Blood Brain Barrier ◽  
Tumor Heterogeneity ◽  
Checkpoint Inhibitors ◽  
Oncolytic Viruses ◽  
Brain Barrier ◽  
Current Status ◽  
Blood Brain ◽  
Federal Authority

Glioblastoma is one of the most difficult tumor types to treat with conventional therapy options like tumor debulking and chemo- and radiotherapy. Immunotherapeutic agents like oncolytic viruses, immune checkpoint inhibitors, and chimeric antigen receptor T cells have revolutionized cancer therapy, but their success in glioblastoma remains limited and further optimization of immunotherapies is needed. Several oncolytic viruses have demonstrated the ability to infect tumors and trigger anti-tumor immune responses in malignant glioma patients. Leading the pack, oncolytic herpesvirus, first in its class, awaits an approval for treating malignant glioma from MHLW, the federal authority of Japan. Nevertheless, some major hurdles like the blood–brain barrier, the immunosuppressive tumor microenvironment, and tumor heterogeneity can engender suboptimal efficacy in malignant glioma. In this review, we discuss the current status of malignant glioma therapies with a focus on oncolytic viruses in clinical trials. Furthermore, we discuss the obstacles faced by oncolytic viruses in malignant glioma patients and strategies that are being used to overcome these limitations to (1) optimize delivery of oncolytic viruses beyond the blood–brain barrier; (2) trigger inflammatory immune responses in and around tumors; and (3) use multimodal therapies in combination to tackle tumor heterogeneity, with an end goal of optimizing the therapeutic outcome of oncolytic virotherapy.

scholarly journals Immune-Related Pancytopenia Induced by Anti-PD-1 Therapy – Interrupt or Continue Treatment – The Role of Immunohistochemical Examination

2019 ◽  
Vol 12 (3) ◽  
pp. 820-828 ◽  
Author(s):  
Bożena Cybulska-Stopa ◽  
Andrzej Gruchała ◽  
Maciej Niemiec
Keyword(s):  
Bone Marrow ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Positive Outcomes ◽  
Hematological Disorders ◽  
Therapeutic Outcomes ◽  
Appropriate Treatment ◽  
Programmed Death

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed death receptor-1/ligand-1 (anti-PD-1/anti-PD-L1) caused a breakthrough in oncology and significantly improved therapeutic outcomes in cancer patients. ICIs generate a specific reaction in T cells, directed against antigens on cancer cells, leading to their damage and death. Through similar or the same antigens, activated lymphocytes may also have a cytotoxic effect on healthy cells, causing development of specific adverse effects – so-called immune-related adverse events (irAEs). We present the case report of a 56 year old patient with disseminated melanoma. During treatment with immunotherapy (anti PD-1), neutropenic fever and pancytopenia occurred. Trepanobiopsy of the bone marrow was performed to determine the cause of pancytopenia. Histopathological assessment of bone marrow combined with immunophenotype investigations may explain the cause of hematological disorders occurring in the course of treatment with ICIs, and support the choice of an appropriate treatment, directly translated into positive outcomes.

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 Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

2020 ◽  
Vol 22 (1) ◽  
pp. 190
Author(s):  
Fulvio Borella ◽  
Mario Preti ◽  
Luca Bertero ◽  
Giammarco Collemi ◽  
Isabella Castellano ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Survival Rates ◽  
Younger Women ◽  
Multiple Tumor ◽  
Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

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