Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy

Lymphoma, which is highly malignant, stems from lymph nodes and lymphoid tissue. Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2), which binds with programmed cell death 1 protein(PD-1) to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance. Recently, immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab) have been introduced into the lymphoma treatment algo...     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.     

免疫检查点抑制剂相关内分泌不良事件

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）是一类新型抗肿瘤药物，通过增强抗肿瘤免疫应答产生抗肿瘤作用，已经在多种恶性肿瘤治疗中表现出显著疗效。由于免疫检查点抑制剂特定的作用靶点和机制，可引起自身免疫和炎症效应，称为免疫相关不良事件（immune-related adverse events，irAEs）。随着免疫检查点抑制剂的广泛应用，其导致的irAEs也越来越受到重视，其中内分泌相关不良事件（如甲状腺功能障碍、垂体炎、肾上腺功能不全等）起病时表现隐匿，不易被发现，导致治疗延误，往往带来严重不良后果甚至危及患者生命。本文将总结既往文献，对免疫检查点抑制剂相关内分泌不良事件的发生率、可能的发病机制、临床表现、诊断等进行述评。     

Comment on “Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy”

We recently read with interest the original research article entitled "Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy". The abovementioned article is an observational retrospective cohort study, which could be of particular value for clinicians to understand how immunotherapy affects pre-existing enteral disease in inflammatory bowel disease patients. Although we appreciate the endeavor of Samuel Rubin et al, based on our in-depth analysis, we detected a potential shortcoming in this article; thus, we present our comments in this letter. If the authors contemplate these comments on their relevant research, we believe that their contribution would be considerable for future studies.     

Combined immune checkpoint inhibitors of CTLA4 and PD-1 for hepatic melanoma of unknown primary origin: A case report

BACKGROUNDMelanoma is uncommonly found in lymph nodes, subcutaneous tissue, or visceral organs without a primary lesion, where it is identified as metastatic melanoma with unknown primary (MUP). Hepatic MUP is extremely rare and has a poor prognosis. There is limited information on its pathogenesis, clinical and imaging features, and pathological findings. There are no guidelines for the use of immune checkpoint inhibitors (ICIs) in hepatic MUP, and the treatment outcome has rarely been reported.CASE SUMMARYA 42-year-old woman presented to our hospital with hepatic tumors found incidentally during a routine check-up. Contrast-enhanced abdominal com-puterized tomography showed multiple mass lesions in the liver. Pathological results revealed melanoma, which was confirmed by immunohistochemical staining for HMB-45(+), Melan-A(+), S-100(+), and SOX10(+). There was no evidence of primary cutaneous, ocular, gastrointestinal, or anal lesion on a comprehensive examination. The patient was diagnosed with hepatic MUP. She received combined antibodies against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, ipilimumab) and programmed death protein-1 (PD-1, nivolumab). She died of hepatic failure 9 mo after hepatic MUP was diagnosed. This the first case of hepatic MUP treated with combined ipilimumab and nivolumab, who showed better outcome than previous cases.CONCLUSIONCombined ICIs of PD-1 and CTLA-4 may be considered as the first-line therapy for patients with hepatic MUP.     

免疫检查点抑制剂的抗肿瘤临床实践与展望

基于靶向免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的肿瘤免疫治疗在近10年取得了重要进展,程序性死亡因子-1(PD-1)/程序性死亡因子配体-1(PD-L1)抗体治疗则成为肿瘤治疗领域最具潜力的新型疗法.中国肿瘤学者与发达国家学者基本同步开展的肿瘤免疫疗法的临床实践,进一步验...     

Biomarkers for immune-related toxicities of checkpoint inhibitors: current progress and the road ahead

Introduction: Immune checkpoint pathways are key immune regulatory pathways that play a physiologic role in maintaining immune-homeostasis and are often co-opted by cancer cells to evade the host immune system. Recent developments in cancer immunotherapy, mainly drugs blocking the immune checkpoint pathways, have revolutionized the treatment paradigm for many solid tumors. A wide spectrum of immune-related adverse events (irAEs) have been described with the use of these agents which necessitate treatment with immunosuppression, lead to disruption of therapy and can on occasion be life-threatening. There are currently no clinically validated biomarkers to predict the risk of irAEs.

Areas covered: In this review, the authors describe the current progress in identifying biomarkers for irAEs and potential future directions. Literature search was conducted using PubMed-MEDLINE, Embase and Scopus. In addition, abstracts from major conference proceedings were reviewed for relevant content.

Expert commentary: The discovery of biomarkers for irAEs is currently in its infancy, however there are a lot of promising candidate biomarkers that are currently being investigated. Biomarkers that can identify patients at a higher risk of developing irAEs or lead to early detection of autoimmune toxicities are crucial to optimize patient selection for immune-oncology agents and to minimize toxicity with their use.     

Research progress and clinical application of predictive biomarker for immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as epochal milestones in the ?eld of anti-cancer immunotherapy. With promising clinical effectiveness, ICIs can significantly prolong the overall survival of patients with advanced cancer of different types. Although their remarkable effectiveness has been demonstrated in clinical application, ICIs display limitations in terms of unique response patterns. Only a subset of patients exhibits objective responses, while others show rapid disease progression. Considering that there is a fair representation of both subsets of patients (responders and non-responders), clinicians ought to effectively stratify patients who will potentially benefit from ICI therapy, and optimize a strategy for patient selection.

Areas covered: In this review, the authors have summarized several key factors involved in the biomarker development of ICI therapy, such as neoantigen production and presentation, the tumor microenvironment, and alternation in specific gene signaling pathways.

Expert opinion: Considering the extreme complexity of the immune system, a single biomarker may fail to appropriately stratify patients for ICI therapy. Therefore, future biomarker research should focus on designing an integrated biomarker system that will successfully guide combination therapies to overcome resistance to immunotherapy.     

Results and challenges of immune checkpoint inhibitors in colorectal cancer

Introduction: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy. Immunotherapy, with the so-called immune checkpoint inhibitors (CPIs), has recently been approved in treatment of multiple cancers due to its prolonged disease control and acceptable toxicities. The recent groundbreaking success involving anti-PD-1 CPIs in metastatic CRC with deficient mismatch repair system (dMMR) is promising, with several trials ongoing. Major challenges are ahead in order to determine how, when and for which patients we should use these CPIs in CRC.

Areas covered: This review highlights some promises and challenges concerning personalized immunotherapy in CRC. First results and ongoing breakthrough trials are presented. The crucial role of biomarkers in selecting patient is also discussed.

Expert opinion: As of now, dMMR and POLE mutations (DNA polymerase ε) with ultramutator phenotype are the most powerful predictive biomarkers of CPI efficacy. The most challenging issue is pMMR mCRC and determination of how to convert a ‘nonimmunogenic’ neoplasm into an ‘immunogenic’ neoplasm, a combination of CPIs with radiation or MEK inhibitor probably being the most relevant strategy. Next-generation sequencing (NGS) assays to quantify mutational load could be more reliable predictive biomarkers of CPIs efficacy than PD-L1 expression or immune scores.     

Programmed cell death protein-1 inhibitor combined with chimeric antigen receptor T cells in the treatment of relapsed refractory non-Hodgkin lymphoma: A case report

BACKGROUNDChimeric antigen receptor T cell (CART) therapy has benefited many refractory lymphoma patients, but some patients experience poor effects. Previous studies have shown that programmed cell death protein-1 (PD-1) inhibitors can improve and prolong the therapeutic effect of CAR-T cell treatment.CASE SUMMARYA 61-year-old male presented with 15-d history of diarrhea and lower-limb edema. A large mass was detected in the pelvis, and pathology indicated non-Hodgkin diffuse large B-cell lymphoma. After three cycles of the R-CHOP chemotherapeutic regimen, the patient showed three subcutaneous nodules under the left armpit and both sides of the cervical spine. Pathological examination of the nodules indicated DLBCL again. The patient was diagnosed with relapsed and refractory diffuse large B-cell lymphoma. We recommended CAR-T cell treatment. Before treatment, the patient’s T cell function and expression of immune detection points were tested. Expression of PD-1 was obviously increased (52.7%) on cluster of differentiation (CD)3+ T cells. The PD-1 inhibitor (3 mg/kg) was infused prior to lymphodepleting chemotherapy with fludarabine and cyclophosphamide. CAR-CD19 T cells of 3 × 10⁶/kg and CAR-CD22 T cells 1 × 10⁶/kg were infused, respectively. The therapeutic effect was significant, and the deoxyribonucleic acid copy numbers of CAR-CD19 T cells and CAR-CD22 T cells were stable. Presently, the patient has been disease-free for more than 12 mo.CONCLUSIONThis case suggests that the combination of PD-1 inhibitors and CAR-T cells improved therapeutic efficacy in B-cell lymphoma.     

Recent Developments in Oncology Immunotherapy,Implications for NPs Part 1

In the past decade, cancer immunotherapies have revolutionized oncology practices. Since the first approval in 2011 of an anticytotoxic T-lymphocyte antigen 4 antibody, immunotherapies have significantly improved patient survival. They differ from traditional chemotherapies in mechanism, action, and toxicity profiles. Immunotherapies may be administered over prolonged periods of time and require vigilant monitoring from the patient’s health care team. This article, part 1 of 2, on immunotherapy aims to provide primary care nurse practitioners with an overview on the categories of immunotherapies, their mechanism of actions, and a brief toxicity profile.     

PD-1抑制剂免疫相关不良反应的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICI)的应用是肿瘤治疗领域的重大突破,是恶性肿瘤患者新的选择和希望。国家食品与药品管理监督局(Chinese Food and Drug Administration,CFDA)批准程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)免疫抑制剂用于多种肿瘤的治疗。但是PD-1抑制剂可引起自身免疫毒性,虽然大多数免疫相关不良反应(immune-related adverse events,irAEs)以1~2级为主,但仍有部分患者发生危及生命的3~4级免疫毒性反应。     

Dynamic changes in the radiologic manifestation of a recurrent checkpoint inhibitor related pneumonitis in a non-small cell lung cancer patient: A case report

BACKGROUNDAs immune checkpoint inhibitors (ICIs) have become widely used in lung cancer treatment, immune-related adverse events (irAEs) warrant sufficient attention. Checkpoint inhibitor-related pneumonitis (CIP) is one of the most concerning adverse events as it is uncommon but life threatening.CASE SUMMARYThe patient whose case is reported here experienced three episodes of CIP in a span of 4 mon. Interestingly, the three episodes of CIP involved different regions of the lung separately. Taking these pneumonitis areas together makes nearly a whole lung area.CONCLUSIONThis case showed that recurrent CIPs may occur repeatedly until the whole lung is involved, suggesting that the follow-up period of CIP should be long enough, and the rechallenge of ICI should be done with due caution.