PD-1/PD-L1 antagonists in gastric cancer: Current studies and perspectives

Immune checkpoints release suppressive signals for T cells, which enable the tumors to escape from immune destruction and provide a new concept that uses the capabilities of the immune system as a therapeutic target for tumors. At present, programmed death receptor 1 (PD-1)/programmed death ligand-1 (PD-L1) has become the most promising therapeutic target. PD-1/PD-L1 blockades exhibit long-lasting antitumor efficacy and safety in patients with various cancers, such as melanoma and non-small-cell lung cancer. Moreover, PD-L1 is highly expressed in the peripheral blood and tumor specimens of patients with cancer, and the expression of PD-L1 is positively correlated with various pathological features and may serve as a predictor of poor prognosis or a diagnostic tool. Clinical trials have verified that PD-1/PD-L1 blockade therapy benefits patients with advanced gastric cancer or gastroesophageal junction cancer. Furthermore, there are many molecules involved in the regulation of PD-1/PD-L1 expression, and the modification of these molecules via drugs and combinations with PD-1/PD-L1 inhibitors may further improve the efficacy of immunotherapy for gastric cancer. In this review, the efficacy, safety, and possible combination treatment options of PD-1/PD-L1 in gastric cancer are reviewed in experimental and clinical settings.     

肿瘤免疫检查点抑制剂相关肺炎的管理

以免疫检查点程序性死亡因子-1（programmed death 1，PD-1）抑制剂、程序性死亡因子配体-1（programmed death ligand 1，PD-L1）抑制剂及细胞毒性T淋巴细胞相关蛋白4（cytotoxic T lymphocyte antigen 4，CTLA-4）抑制剂为代表的肿瘤免疫治疗，近年来在肿瘤治疗中广泛开展，有效延长了肿瘤患者的生存期，但也可能导致免疫治疗相关不良事件（immune-related adverse events，irAEs）。免疫检查点抑制剂（immune checkpoint inhibitor，ICIs）相关肺炎是常见的irAEs之一，可导致部分肿瘤患者治疗暂停、治疗失败、甚至威胁生命。正确了解ICIs相关肺炎的临床特点，早期诊断并恰当治疗，对影响肿瘤患者的预后、延长生命有重要意义。     

Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues

A combination of anti–CTLA-4 plus anti–PD-1/PD-L1 is the most effective cancer immunotherapy but causes high incidence of immune-related adverse events (irAEs). Here we report that targeting of HIF-1α suppressed PD-L1 expression on tumor cells and tumor-infiltrating myeloid cells, but unexpectedly induced PD-L1 in normal tissues by an IFN-γ–dependent mechanism. Targeting the HIF-1α/PD-L1 axis in tumor cells reactivated tumor-infiltrating lymphocytes and caused tumor rejection. The HIF-1α inhibitor echinomycin potentiated the cancer immunotherapeutic effects of anti–CTLA-4 therapy, with efficacy comparable to that of anti–CTLA-4 plus anti–PD-1 antibodies. However, while anti–PD-1 exacerbated irAEs triggered by ipilimumab, echinomycin protected mice against irAEs by increasing PD-L1 levels in normal tissues. Our data suggest that targeting HIF-1α fortifies the immune tolerance function of the PD-1/PD-L1 checkpoint in normal tissues but abrogates its immune evasion function in the tumor microenvironment to achieve safer and more effective immunotherapy.     

程序性死亡因子-1抑制剂在血液系统恶性肿瘤治疗中的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用是一种新型免疫治疗手段。阻断程序性死亡因子-1(programmed death 1,PD-1)与其配体(PD-L1)结合,可避免免疫逃逸,恢复机体免疫应答,发挥其抗肿瘤效应,是目前抗肿瘤治疗中炙手可热的方法之一。PD-1抑制剂在越来越多的实体瘤治疗中表现出较好疗效,但在血液系统恶性肿瘤中的应用仍相对有限。本文回顾PD-1抑制剂在血液系统恶性肿瘤中的临床研究,探讨其临床应用前景。     

Development of cancer immunotherapy based on PD-1/PD-L1 pathway blockade

Programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy has achieved considerable success in various tumours. However, only a fraction of patients benefit from its clinical application, and some patients might be suffer from tumour resistance against PD-1/PD-L1 blockade therapy after the original response. In this review, we summarized the main reasons that caused the low response rate of PD-/PD-L1 blockade therapy: firstly, the off-target of PD-1/PD-L1 blocking agents, which is also the main factor of the side effect of autoimmune disorders; secondly, the insufficient infiltration of T cells in a tumour microenvironment; thirdly, the low immunogenicity of tumor cells; fourth, other immunosuppressive components impairing the therapeutic efficacy of the immunotherapy based on the PD-/PD-L1 blockade, and introducing some updated the delivery system of PD-1/PD-L1 blocking agents and the combination therapy based on PD-1/PD-L1 inhibitors and other therapeutics that can complement and promote each other to achieve improved immune response.

The possible reasons that caused low response rate and severe side effects of programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy and corresponding strategies.     

Personalized Immuno-Oncology

Cancer immunotherapy, which aims to control the immune system to eradicate cancer cells and prevent their spread, needs to be personalized because anticancer immune responses can be inhibited in several ways that vary from patient to patient. Cancer immunotherapy includes pharmaceuticals such as immune checkpoint inhibitors and monoclonal antibodies (MAbs) as well as cell therapy, immunogene therapy, and vaccines. Combination of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) drugs with other immunotherapy drugs, for example, antibody-drug conjugates, as well as combination of PD-1/PD-L1 drugs with other therapies, for example, chemotherapy and radiation therapy, are being explored. Biomarkers are important for predicting the response to immunotherapy. Molecular diagnostics and sequencing are important technologies for guiding treatment in immuno-oncology. Genomic profiling of tumor mutational burden may enhance the predictive utility of PD-L1 expression and facilitate personalized combination immunotherapy. Optimization of personalized immuno-oncology requires integration of several technologies and selection of those best suited for an individual patient. Advances in immuno-oncology are also attributed to technologies for targeted delivery of anticancer therapeutics such as antigen-capturing nanoparticles for precision targeting and selective delivery. A breakthrough in cell therapy of cancer is a chimeric antigen receptors-T cell, which combines the antigen-binding site of a MAb with the signal activating machinery of a T cell, freeing antigen recognition from major histocompatibility complex restriction. Gene-editing tools such as clustered regularly interspaced short palindromic repeats have a promising application for removing alloreactivity and decreasing immunogenicity of third-party T cells. In conclusion, personalized immuno-oncology is one of the most promising approaches to management of cancer.     

晚期非小细胞肺癌免疫治疗进展

肺癌是我国最常见的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)约占85%,且大部分NSCLC患者在确诊时疾病已进展至晚期,病死率较高。近年来,临床对于晚期NSCLC的治疗已从传统的手术治疗、化学治疗、放射治疗、靶向治疗走向了免疫治疗。免疫检查点抑制剂(ICIs)治疗晚期NSCLC体现出了良好的抗肿瘤活性,尤其体现在细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性死亡受体-1(PD-1)、程序性死亡配体-1(PD-L1)抑制剂。基于此,本文将重点综述CTLA-4、PD-1、PD-L1抑制剂在晚期NSCLC中的治疗进展,以期提高患者的临床获益率,为临床选择合理治疗方案提供参考。     

参与调控细胞程序性死亡蛋白1及其配体1信号通路的研究进展

细胞程序性死亡蛋白1及其配体1(PD-1/PD-L1)通路已经成为研究热点,无论在抗肿瘤还是在抗炎方面均取得了一定的成果,但具体的机制目前尚不完全清楚。本文介绍了PD-1及PD-L1的分子结构、功能以及与其他通路之间的关系。PD-1蛋白是免疫抑制分子,与其配体PD-L1结合起促进细胞凋亡的作用。在肿瘤或炎症中,JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等其他信号通路被激活,诱导免疫细胞及肿瘤细胞高表达PD-1及PD-L1,使免疫细胞活性降低,消耗增加,募集减少,从而使机体抗肿瘤、抗炎能力下降。PD-1/PD-L1与JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等其他信号通路也起相互调控作用。PD-1/PD-L1抑制剂与JAK/STAT、NF-κB、MAPK、PI3K以及TIM-3/Gal-9等通路抑制剂联合应用,在抗肿瘤以及肿瘤耐药性方面取得了突破性进展。然而,相对于PD-1/PD-L1对肿瘤作用的研究而言,PD-1/PD-L1在炎症方面的研究相对较少,无相应的药物应用于临床,需要大量的基础研究支持。     

Pembrolizumab for the treatment of diffuse large B-cell lymphoma

ABSTRACT

Introduction: Pembrolizumab is a novel monoclonal antibody that targets the interaction between programmed cell death protein 1 (PD-1) and its ligand (PD-L1). Pembrolizumab has shown significant clinical efficacy in Hodgkin Lymphoma (HL), but results in non Hodgkin Lymphoma (NHL) are mixed. Some NHL subtypes, which share certain genetic features with HL, such as alterations in chromosome 9p24.1 and expression of PD-L1, have shown promising responses in early phase trials.

Areas covered: In this review, we provide an overview of pembrolizumab as a compound, and present the available clinical efficacy and safety data in the treatment of diffuse large B cell lymphomas.

Expert opinion: Current early phase data suggest that single agent pembrolizumab in NHL demonstrates both efficacy and a favorable safety profile. However, it is anticipated that future treatment strategies will be biomarker-driven and incorporate pembrolizumab into combination therapies with chemotherapy and/or immunotherapy agents.     

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。     

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...     

Diabetic ketoacidosis induced by a single dose of pembrolizumab

Immune checkpoint inhibitors are a new class of anticancer drugs recently approved by the US Food and Drug Administration (FDA) for the treatment of various malignancies. Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death protein-1 (PD-1) receptor and blocks its interaction with programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). Pembrolizumab was first approved by the FDA in 2014 for the treatment of advanced melanoma and is currently approved for use in non-small cell lung cancer and several other neoplasms. Immune checkpoint inhibitors such as pembrolizumab have been reported to induce immune-mediated side effects, including type 1 diabetes mellitus in very rare cases (0.1% in clinical trials). Here, we report the case of a woman with no known history of diabetes who presented to our emergency department in a state of diabetic ketoacidosis within 3?weeks of receiving only a single dose of pembrolizumab therapy, and without any previous exposure to immunotherapy. This case of abrupt adult-onset type 1 diabetes mellitus is an example of the undesirable side effects that can emerge after only a brief exposure to an immune checkpoint inhibitor. Close monitoring of patients receiving immune checkpoint inhibitors is warranted for the early diagnosis and management of imminent and potentially life-threatening complications.     

Efficacy and Safety of Programmed Cell Death 1 Inhibitor Monotherapy Versus Chemotherapy as Second-Line Treatment for Advanced Esophageal Cancer: A Meta-analysis and Systematic Review

PurposeWith programmed cell death 1 (PD-1) inhibitors approved for second-line treatment of advanced esophageal cancer, immunotherapy and chemotherapy have gradually become the main treatments for second-line treatment of patients with advanced esophageal cancer (AEC). This meta-analysis and systematic review were conducted to evaluate the efficacy and safety of PD-1 inhibitors monotherapy versus chemotherapy in second-line treatment of AEC.MethodsEligible randomized controlled trials were searched in PubMed, Embase, and the Cochrane Library and abstracts presented at the American Society of Clinical Oncology or European Society of Medical Oncology were reviewed to assess the efficacy and tolerability of PD-1/programmed cell death ligand 1 (PD-L1) inhibitors relative to chemotherapy for AEC from January 2016 to October 2020. Patients diagnosed with AEC and progressing after first-line therapy were included in this study. Hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), risk ratios (RRs) of objective response rate (ORR), and the odds ratios (ORs) of adverse effects (AEs) were calculated.FindingsThe study included 4 randomized controlled trials with 1683 patients. The results indicated that PD-1 inhibitors prolonged the OS (HR = 0.79; 95% CI, 0.71–0.88; P < 0.01) and improved the ORR (RR = 3.00; 95% CI, 2.36–3.82; P = 0.01) but did not improve the PFS (HR = 0.96; 95% CI, 0.76–1.20; P = 0.692) compared with chemotherapy in the second-line treatment of AEC. PD-1 inhibitors alone were associated with a lower incidence of all treatment-related AEs (OR = 0.29; 95% CI, 0.09–0.89; P = 0.03) and grade 3 to 5 treatment-related AEs (OR = 0.26; 95% CI, 0.16–0.44; P < 0.01) versus chemotherapy. PD-1 inhibitors prolonged OS mainly in the following patient groups: male, age <65 years, Eastern Cooperative Oncology Group performance status of 1, or PD-L1 tumor proportion score ≥10%. Asian patients had a longer OS than non-Asian patients (P = 0.01).ImplicationsThe available evidence indicates that the efficacy and tolerability of PD-1 inhibitors were better than chemotherapy in the second-line treatment of AEC, and the benefiting population of these patients was limited to males, those <65 years of age, those with a Eastern Cooperative Oncology Group performance status of 1, or those with a PD-L1 tumor proportion score ≥10%. Notably, Asian patients receiving immune monotherapy had longer OS than non-Asian patients.     

Atezolizumab-induced anaphylactic shock in a patient with hepatocellular carcinoma undergoing immunotherapy: A case report

BACKGROUNDAtezolizumab is a programmed death ligand 1 (PD-L1) inhibitor, and its combination with bevacizumab has been proven an effective immunotherapy for unresectable hepatocellular carcinoma (HCC). Treatment with immune checkpoint inhibitors (ICIs) can lead to hypersensitivity reactions; however, anaphylactic shock is rare. We present a case of life-threatening anaphylactic shock during atezolizumab infusion and performed a relevant literature review.CASE SUMMARYA 75-year-old man was diagnosed with HCC recurrence after hepatectomy. He was administered immunotherapy with atezolizumab plus bevacizumab after an allergy to a programmed death-1 (PD-1) inhibitor. The patient showed a sudden onset of dizziness, numbness, and lack of consciousness with severe hypotension during atezolizumab infusion. The treatment was stopped immediately. The patient’s symptoms resolved after 5 mg dexamethasone was administered. Because of repeated hypersensitivity reactions to ICIs, treatment was changed to oral targeted regorafenib therapy. CONCLUSIONFurther research is necessary for elucidating the hypersensitivity mechanisms and establishing standardized skin test and desensitization protocols associated with PD-1 and PD-L1 to ensure effective treatment with ICIs.     

Immunomodulators targeting the PD-1/PD-L1 protein-protein interaction: From antibodies to small molecules

Cancer immunotherapy has made great strides in the recent decade, especially in the area of immune checkpoint blockade. The outstanding efficacy, prolonged durability of effect, and rapid assimilation of anti-PD-1 and anti-PD-L1 monoclonal antibodies in clinical practice have been nothing short of a medical breakthrough in the treatment of numerous malignancies. The major advantages of these therapeutic antibodies over their small molecule counterparts have been their high binding affinity and target specificity. However, antibodies do have their flaws including immune-related toxicities, inadequate pharmacokinetics and tumor penetration, and high cost burden to manufacturers and consumers. These limitations hinder broader clinical applications of the antibodies and have heightened interests in developing the alternative small molecule platform that includes peptidomimetics and peptides to target the PD-1/PD-L1 immune checkpoint system. The progress on these small molecule alternatives has been relatively slow compared to that of the antibodies. Fortunately, recent structural studies of the interactions among PD-1, PD-L1, and their respective antibodies have revealed key hotspots on PD-1 and PD-L1 that may facilitate drug discovery efforts for small molecule immunotherapeutics. This review is intended to discuss key concepts in immuno-oncology, describe the successes and shortcomings of PD-1/PD-L1 antibody-based therapies, and to highlight the recent development of small molecule inhibitors of the PD-1/PD-L1 protein-protein interaction.     

免疫检查点抑制剂相关心肌炎分子机制研究进展

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已成为目前应用最广的恶性肿瘤免疫疗法，主要包括CTLA-4（cytotoxic T lymphocyte associated antigen-4）抑制剂、PD-1/PD-L1（programmed death protein-1/ligand-1）抑制剂和LAG-3（lymphocyte activation gene-3）抑制剂。ICIs导致的最致命的免疫相关不良反应（immune-related adverse events, irAE）之一为免疫检查点抑制剂相关的心肌炎（immune checkpoint inhibitor-associated myocarditis, ICIAM）。ICIs联合治疗时ICIAM的发病率多高于单药治疗。其分子机制主要包括免疫检查点作为新抗原、肿瘤同源抗原的异位识别、免疫检查点心脏保护的阻断、自身抗体和炎症因子的产生以及微生物的调节作用等。目前已有多种治疗ICIAM药物及非药物性方案。对于ICIAM分子机制的探索和治疗管理方案的进步仍需多学科共同努力。     

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.     

Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients

Introduction  

Studies on the role of programmed death-1(PD-1) and its main ligand (PD-L1) during experimental models of sepsis have shown that the PD-1/PD-L1 pathway plays a pathologic role in altering microbial clearance, the innate inflammatory response and accelerated apoptosis in sepsis. However, the expression of PD-1 and PD-L1 and their role during the development of immune suppression in septic patients have not been elucidated. The present study was designed to determine whether the expression of PD-1 and PD-L1 is upregulated in septic shock patients and to explore the role of this pathway in sepsis-induced immunosuppression.     

Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies

The use of tumor-specific monoclonal antibodies (MAbs) has revolutionize the field of cancer immunotherapy. Although treatment of malignant diseases with MAbs is promising, many patients fail to respond or relapse after an initial response. Both solid tumors and hematological malignancies develop mechanisms that enable them to evade the host immune system by usurping immune checkpoint pathways such as PD-1, PD-2, PDL-1, or PDL-2 (programmed cell death protein-1 or 2 and PD-Ligand 1 or 2), which are expressed on activated T cells and on T-regulatory, B cells, natural killers, monocytes, and dendritic cells. One of the most exciting anticancer development in recent years has been the immune checkpoint blockade therapy by using MAbs against immune checkpoint receptor and/or ligands. Anti-PD1 antibodies have been tested in clinical studies that included patients with hematological malignancies and showed remarkable efficacy in Hodgkin lymphoma (HL). In our review, we will focus on the effect of PD-1 activation on hematological malignancies and its role as a therapeutic target.

• Key messages

• The programmed death 1 (PD1) immune checkpoint is an important homeostatic mechanism of the immune system that helps in preventing autoimmunity and uncontrolled inflammation in cases of chronic infections.

• However, PD1 pathway is also operated by a wide variety of malignancies and represents one of the most important mechanisms by which tumor cells escape from the surveillance of the immune system.

• Blocking of immune checkpoints by the use of monoclonal antibodies opened a new era in the field of cancer immunotherapy. Results from clinical trials are promising, and currently, this approach has been proven effective and safe in patients with solid tumors and hematological malignancies.

     

Pembrolizumab for the first-line treatment of non-small cell lung cancer

Introduction: Platinum-based chemotherapy had long played a role as standard therapy for the first-line treatment of advanced or recurrent non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors such as pembrolizumab, a monoclonal antibody that prevents programmed death protein 1 (PD-1) receptor, have brought a paradigm shift in this field.

Areas covered: In this article, we review the relevant literatures and ongoing trials on the first-line treatment of pembrolizumab. Especially, in two pivotal phase III trials, KEYNOTE-024 and ?189, both pembrolizumab monotherapy and combined pembrolizumab plus chemotherapy significantly prolonged overall survival (OS) compared to the existing platinum-based chemotherapy. Currently, multiple trials with combination therapy of pembrolizumab and other agents have been conducted, and further evidences are expected to be created.

Expert opinion: Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway are essential drugs for advanced or recurrent NSCLC, among which pembrolizumab becomes one of the standards of care in the first-line of NSCLC. For further improvement in efficacy of pembrolizumab, it is necessary to clarify the identification of biomarkers exclusive to PD-L1 expression, predictive factors for patients who benefit most from the agent.