A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now

The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette–Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. Several checkpoint targets (programmed death ligand-1 [PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in immune system functioning.     

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer

The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.     

结直肠癌免疫检查点治疗的研究进展

目前免疫治疗正在非小细胞肺癌、黑色素瘤、膀胱癌等各个瘤种中如火如荼地开展,其治疗方法也多种多样,包括肿瘤疫苗治疗、过继性T细胞疗法、免疫检查点抑制剂治疗等,但目前结直肠癌免疫治疗主要集中于免疫检查点抑制剂(PD-1/PD-L1及CTLA-4抑制剂等).自从PD-1/PD-L1抑制剂在dMMR/MSI-H晚期结直肠癌患者...     

Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions

In recent years, there has been dramatic expansion of the treatment armamentarium for patients with advanced renal cell carcinoma (aRCC), including drugs targeting vascular endothelial growth factor and mammalian target of rapamycin (mTOR) pathways. Despite these advances, patient outcomes remain suboptimal, underscoring the need for therapeutic interventions with novel mechanisms of action. The advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment landscape for several solid malignancies. Specifically, drugs targeting the programmed death 1 (PD-1) and cytotoxic T-lymphocyte associated antigen (CTLA-4) pathways have demonstrated considerable clinical efficacy and gained regulatory approval as single-agent or combination therapy for the treatment of patients with metastatic melanoma, non-small cell lung cancer, aRCC, advanced squamous cell carcinoma of the head and neck, urothelial cancer and Hodgkin lymphoma. In aRCC, the PD-1 inhibitor nivolumab was approved in both the United States and Europe for the treatment of patients who have received prior therapy, based on improved overall survival compared with the mTOR inhibitor everolimus. Other checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab in combination with several agents, and the PD-L1 inhibitor atezolizumab, are in various stages of clinical development in patients with aRCC. In this review, current evidence related to the clinical use of checkpoint inhibitors for the treatment of patients with aRCC is discussed, including information on the frequency and management of unconventional responses and the management of immune-related adverse events. In addition, perspectives on the future use of checkpoint inhibitors are discussed, including the potential value of treatment beyond progression, the potential use in earlier lines of care or in combination with other agents, and the identification of biomarkers to guide patient selection and enable individualization of therapy.     

Cutaneous adverse effects of the immune checkpoint inhibitors

The immune checkpoint targeted agents, anti–cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and anti–programed cell death 1 (PD-1) or anti–programmed death ligand 1 (PD-L1) inhibitors are frequently associated with cutaneous side effects that are often dose limiting and can lead to discontinuation of therapy. Ipilimumab, a CTLA-4 inhibitor, is most commonly associated with a morbilliform eruption on the trunk and extremities and pruritus. More severe cutaneous toxicities reported include toxic epidermal necrolysis and severe drug rash with eosinophila and systemic symptoms. Recent case reports of Sweet syndrome and cutaneous sarcoidosis have also recently been described after treatment with ipilimumab. The cutaneous events usually occur early in the course of treatment and are dose dependent. PD-1 inhibitors, nivolumab and pembrolizumab, induce similar but less severe toxicities compared with the CTLA-4 inhibitors. The most common cutaneous adverse events include lichenoid reactions, eczema, vitiligo, and pruritus. Lichenoid oral mucosal lesions located on the tongue, buccal mucosa, lips, or gingivae or located on all of these have also recently been described. The time of onset of the cutaneous events with the PD-1 inhibitors occurs later than that seen with the CTLA-4 inhibitors. Anti–PD-L1 antibodies, such as atezolizumab, have a similar side effect profile compared with the PD-1 inhibitors. Combination of immune checkpoint inhibitors, ipilimumab and nivolumab, has recently been approved for the treatment of advanced melanoma. The combination therapy is associated with a more severe side effect profile compared with the agents used as monotherapy. We discuss the most frequently encountered cutaneous side effects of the immune checkpoint inhibitors and review the recommended management strategies.     

PD-1/PD-L1抑制剂相关的内分泌紊乱及其治疗的研究进展

免疫检查点治疗是肿瘤治疗的新模式,目前国内外已有多种免疫检查点单抗药物即程序性细胞死亡蛋白-1（PD-1）及其配体（PD-L1）抑制剂获批进入临床,在恶性黑色素瘤、肺癌、膀胱癌、淋巴瘤等多种肿瘤中得到了广泛应用,但随着PD-1/PD-L1抑制剂在临床上的逐步推广应用,其引起的各种免疫相关不良反应引起了广泛关注,特别是近年来国内外均有多个内分泌腺体受损的相关不良反应报道。本文对PD-1/PD-L1抑制剂治疗引起的各内分泌腺体相关不良反应研究现状以及对应临床处理方法作一综述。     

Next generation predictive biomarkers for immune checkpoint inhibition

With the advent of targeted therapies, there has been a revolution in the treatment of cancer across multiple histologies. Immune checkpoint blockade has made it possible to take advantage of receptor-ligand interactions between immune and tumor cells in a wide spectrum of malignancies. Toxicity in healthy tissue, however, can limit our use of these agents. Immune checkpoint blockade has been approved in advanced melanoma, renal cell cancer, non-small cell lung cancer, relapsed refractory Hodgkin’s lymphoma, and urothelial cancer. Though FDA-approved indications for use of some of these novel agents depend on current protein-based programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) assays, detection methods come with several caveats. Additional predictive tools must be interrogated to discern responders from non-responders. Some of these include measurement of microsatellite instability, PD-L1 amplification, cluster of differentiation 8 (CD8) infiltrate density, and tumor mutational burden. This review serves to synthesize biomarker detection at the DNA, RNA, and protein level to more accurately forecast benefit from these novel agents.     

PD-1/PD-L1抑制剂在膀胱癌新辅助治疗中的应用进展

膀胱癌是一种泌尿系统常见的肿瘤,单纯根治切除手术治疗的患者面临较高复发和转移风险,5年生存率为60~80%。在减少复发、转移和延长生存期的探索中,指南推荐以顺铂为基础的化疗作为标准新辅助治疗。但部分患者无法耐受化疗或对化疗不敏感,新辅助治疗应用率较低,未广泛开展。程序性死亡因子1(PD-1)和程序性死亡因子配体1(PD-L1)是重要的免疫检验点共抑制分子,通过抑制T细胞的激活和增殖通路参与肿瘤的免疫逃逸。近年来一批PD-1/PD-L1抑制剂被批准用于局晚期膀胱癌的一线、二线治疗,疗效及安全性得到证实,因此一些最新的研究探索将PD-1/PD-L1抑制剂运用于新辅助治疗。本文主要对近年来相关研究进行了回顾与总结,探讨PD-1/PD-L1抑制剂在膀胱癌新辅助治疗应用的前景和可能发展的方向。     

PD-1／PD-L1受体抑制剂与肾癌免疫治疗的研究进展

肾癌对放化疗均不敏感,现有治疗手段难以取得理想效果,亟需探究新的治疗方法。程序性死亡因子1（PD-1）和程序性死亡因子配体1（PD-L1）是一对免疫共刺激因子,PD-1、PD-L1高表达与肿瘤免疫治疗及预后密切相关。PD-1及PD-L1阻滞剂在恶性黑色素瘤、非小细胞肺癌的治疗中已取得显著成效,在其他恶性肿瘤中的疗效亦在不断研究中。相关临床研究显示抗PD-1／PD-L1治疗在肾癌中显现一定疗效。PD-1／PD-L1阻滞剂有望成为肾癌治疗的新希望。本文旨在回顾及总结近年来PD-1及PD-L1阻滞剂在肾癌中的应用及研究进展,并探讨其可能的分子机制。     

Combination Treatment of the Oral CHK1 Inhibitor,SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC

IntroductionDespite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.Methods and ResultsHere, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti–programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti–PD-L1/anti–PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10.ConclusionsGiven that anti–PD-L1/anti–PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.     

Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy

Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been immensely successful in the treatment of cancer. Among several checkpoint receptors of immune cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints for cancer immunotherapy. Six drugs including one CTLA-4 blocker (ipilimumab), two PD-1 blockers (nivolumab and pembrolizumab) and three PD-L1 blockers (atezolizumab, avelumab and durvalumab) are approved for the treatment of different types of cancers including both solid tumors such as melanoma, lung cancer, head and neck cancer, bladder cancer and Merkel cell cancer as well as hematological tumors such as classic Hodgkin's lymphoma. The main problem with checkpoint blockers is that only a fraction of patients respond to the therapy. Insufficient immune activation is considered as one of the main reason for low response rates and combination of checkpoint blockers has been proposed to increase the response rates. The combination of checkpoint blockers was successful in melanoma but had significant adverse events. A combination that is selected based on the mechanistic differences between checkpoints and the differences in expression of checkpoints and their ligands in the tumor microenvironment could have a synergistic effect in a given cancer subtype and also have a manageable safety profile. This review aims to help in design of optimal checkpoint blocker combinations by discussing the mechanistic details and outlining the subtle differences between major checkpoints targeted for cancer immunotherapy.     

PD-1/PD-L1抑制剂在恶性黑色素瘤（新）辅助治疗中的研究进展

恶性黑色素瘤是一种具有较高复发率及死亡率的实体肿瘤。目前针对Ⅱ~Ⅲ期黑色素瘤的治疗仍是以外科手术为主,由于缺乏有效的（新）辅助治疗手段,高危黑色素瘤患者的5年生存率仅有30%~70%。程序性死亡因子1（PD-1）和程序性死亡因子配体1（PD-L1）是重要的免疫检验点共抑制分子,通过抑制T细胞的激活和增殖通路参与了肿瘤的免疫逃逸。近些年来包括Nivolumab和Pembrolizumab在内的多种PD-1/PD-L1抑制剂研发获批上市,并在晚期黑色素瘤的治疗中表现出显著的疗效。因此多项针对PD-1/PD-L1抑制剂在高危黑色素瘤患者（新）辅助治疗的临床试验正积极开展。本文主要对近年来相关研究进行了回顾与总结,探讨PD-1/PD-L1抑制剂在黑色素瘤（新）辅助治疗应用的前景和可能发展的方向。     

抗PD-1/PD-L1免疫检查点抑制剂的皮肤免疫相关不良反应的研究进展

随着免疫检查点抑制剂（immune checkpoint inhibitors,ICPI）在国内外临床试验和应用中的逐步推广,越来越多的患者从免疫治疗中获得显著的疗效。其中抗程序细胞死亡蛋白1（programmed death-1,PD-1）及其配体（PD-1 ligand,PD-L1）免疫检查点抑制剂已被美国食品药品管理局（FDA）批准用于恶性黑色素瘤、转移性鳞状非小细胞肺癌、晚期肾癌、头颈鳞状细胞癌、尿路上皮癌等肿瘤的治疗。但PD-1/PD-L1单抗也会引起免疫相关性皮肤、消化道、肝脏、内分泌、肺部等器官的不良反应,皮肤毒性如皮疹、白癜风、皮肤干燥症等是最常见也是最早发生的不良反应。     

The promising role of nivolumab in renal cell cancers

The therapeutic efficacy of checkpoint inhibitors across numerous tumor types has resulted in approval for neoplasms such as melanoma and lung cancer. Nivolumab is a fully humanized IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells. Motzer and Colleagues published the findings of Nivolumab versus everolimus in advanced kidney cancer in the November issue of the New England Journal of Medicine. This trial showed that nivolumab resulted in better median overall survival of 25 months compared to everolimus at 19.6 months, with a hazard ratio for death at 0.73, meeting pre-specified criterion for superiority in favor of nivolumab. These findings mark the defining beneficial role of immune checkpoint inhibitor therapy in metastatic kidney cancer.     

晚期胃癌免疫检查点抑制剂治疗的临床研究进展

[摘要] 晚期胃癌治疗方法有限,预后较差。2017 年,针对程序性死亡蛋白-1（programmed cell death protein-1, PD-1）和程序性死亡配体-1（programmed death ligand-1, PD-L1）的免疫检查点抑制剂获批用于晚期胃癌治疗,提示胃癌免疫治疗时代已经到来。然而,相对于肺癌,免疫检查点抑制剂尚未获批用于胃癌一、二线治疗。目前,大量胃癌免疫治疗临床试验正在进行中,其模式还在进一步优化,包括免疫联合化疗、免疫检查点抑制剂联合其他免疫治疗及新型免疫检查点抑制剂的应用等,同时寻找合适的肿瘤标志物,筛选优势人群用于胃癌精准免疫治疗。本文着重讨论晚期胃癌免疫检查点抑制剂治疗的临床研究最新进展。     

Emerging therapeutic strategies for enhancing sensitivity and countering resistance to programmed cell death protein 1 or programmed death-ligand 1 inhibitors in non–small cell lung cancer

The availability of agents targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint has transformed treatment of advanced and/or metastatic non–small cell lung cancer (NSCLC). However, a substantial proportion of patients treated with these agents do not respond or experience only a brief period of clinical benefit. Even among those whose disease responds, many subsequently experience disease progression. Consequently, novel approaches are needed that enhance antitumor immunity and counter resistance to PD-(L)1 inhibitors, thereby improving and/or prolonging responses and patient outcomes, in both PD-(L)1 inhibitor-sensitive and inhibitor-resistant NSCLC. Mechanisms contributing to sensitivity and/or resistance to PD-(L)1 inhibitors in NSCLC include upregulation of other immune checkpoints and/or the presence of an immunosuppressive tumor microenvironment, which represent potential targets for new therapies. This review explores novel therapeutic regimens under investigation for enhancing responses to PD-(L)1 inhibitors and countering resistance, and summarizes the latest clinical evidence in NSCLC.     

肿瘤免疫治疗中不可忽视的免疫相关不良反应

免疫检查点抑制剂已在我国被批准进入临床应用,随之而来的免疫相关不良反应(irAE)需引起临床医师的关注。文章总结了针对抗程序性细胞死亡蛋白和程序性细胞死亡蛋白配体抗体引起的irAE发病率、特征性临床表现以及治疗方法,探讨了其可能的发病机理、不同类型恶性肿瘤发病率的差别、影响因素以及未来的研究方向,为临床肿瘤医师对肿瘤irAE的识别和监控加以指导。     

Current situation of programmed cell death protein 1/programmed cell death ligand 1 inhibitors in advanced triple-negative breast cancer

Triple-negative breast cancer(TNBC) has the worst prognosis among all molecular types of breast cancer. Because of the strong immunogenicity of TNBC cells, programmed death 1/programmed death ligand 1(PD-1/PD-L1)inhibitors, two kinds of immune checkpoint blockade agents, might help improve the prognosis of TNBC.However, how to better use PD-1/PD-L1 inhibitors and select patients who may benefit from treatment options remains controversial. This article summarizes published clinical studies in wh...     

PD-1/PD-L1抑制剂在尿路上皮癌治疗中的研究进展

近年来,随着人们对肿瘤免疫生物学认识的不断深入,针对免疫检查点抑制的系统免疫疗法在尿路上皮癌领域得到了广泛的探索和临床应用。程序性细胞死亡受体1(programmed death 1,PD-1)及其配体(programmed death ligand 1,PD-L1)是机体免疫活性的重要负性调节因子,可防止正常组织和自身免疫功能的破坏。迄今为止,美国食品和药物管理局(Food and Drug Administration,FDA)已批准了可阻断PD-1(Pembrolizumab和Nivolumab)或PD-L1(Atezolizumab、Durvalumab和Avelumab)的五种免疫检查点抑制剂,根据在相关临床试验中观察到的持久的治疗反应和可控的安全性,用于局部晚期或转移性尿路上皮癌的一线或二线治疗。本文就PD-1/PD-L1抑制剂在尿路上皮癌中的研究进展作一综述。     

Targeting the PD-1/PD-L1 axis in non–small cell lung cancer

The last decade has witnessed rapid advances in the discovery and development of immune checkpoint inhibitors in cancer medicine, particularly drugs targeting programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in non–small cell lung cancer (NSCLC). The proven antitumor efficacy coupled with low rates of drug-related toxicities observed, albeit idiosyncratic, with these novel immunotherapeutics have led to the registration of multiple PD-1 and PD-L1 inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, in second-line advanced NSCLC, whereas durvalumab and avelumab are in late-phase clinical testing. Moreover, pembrolizumab has shown a survival advantage in the first-line setting; however, nivolumab failed to show a survival benefit possibly relating to patient selection based on PD-L1 expression. Current patient selection is based on PD-L1 expression, using the relevant companion diagnostic test, where patients with strong PD-L1 expression being more likely to respond to these novel agents. Ongoing clinical research focuses on the development of PD-1 and PD-L1 inhibitor monotherapy in neoadjuvant and adjuvant NSCLC. There is also much interest in using these drugs as a therapeutic backbone for rational combinations with other treatment modalities including cytotoxic chemotherapies in the first-line NSCLC, other immunotherapies such as cytotoxic T-lymphocyte–associated protein 4 antagonists, molecularly targeted agents including EGFR and ALK inhibitors, and radiotherapy. Concurrent treatment with radiotherapy is of particular interest owing to the potential for the abscopal effect, using radiotherapy to facilitate systemic treatment.