Tocilizumab for the treatment of chimeric antigen receptor T cell-induced cytokine release syndrome

ABSTRACT

Introduction: Cancer-directed immunotherapies are transforming the landscape in oncology as new and exciting therapies move from the laboratory to the bedside. Chimeric antigen receptor T (CAR-T) cells are one of these novel therapies, demonstrating impressive efficacy against B-cell malignancies. With the development of new therapies, it is not uncommon to identify new and unanticipated toxicities. CAR-T cells cause unique toxicities not typically found with traditional cytotoxic chemotherapy or small molecule inhibitors.

Areas covered: CAR-T cell associated toxicities include cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES), alternatively known as immune effector cell-associated neurotoxicity syndrome (ICANS). Prompt identification and management of CRS and CRES are imperative for the prevention of life-threatening complications of these innovative therapies. This literature review describes the seminal trials of CD19-directed immunotherapy and the pathophysiology and management of the toxicities found with CAR-T cells. In addition, the use of the interleukin-6 receptor antibody tocilizumab for CRS is reviewed.

Expert opinion: This review describes the recommended management of CRS and CRES and examines the current limitations in management. Alternative therapies for the treatment of CAR-T cell related toxicities are also explored. Furthermore, the review proposes future directions for research.     

Cellular therapy: Immune‐related complications

The advent of chimeric antigen receptor T (CAR‐T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized “living therapy” is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR‐T. The overwhelming release of cytokines and chemokines by activated CAR‐T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. Tocilizumab, an anti‐IL6 receptor antibody, was recently FDA approved for treatment of CRS after CAR‐T based on its ability to mitigate CRS in many patients. Unfortunately, some patients are refractory and additional therapies are needed. Patients treated with CAR‐T can also develop neurotoxicity and, as the biology is poorly understood, current therapeutic interventions are limited to supportive care. Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR‐T‐related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR‐T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR‐T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.     

胱蛋白酶抑制剂超家族成员CRES的研究进展

胱蛋白酶抑制剂相关的附睾精子发生(cystain-related epididymal spermatogenic,CRES)蛋白是胱蛋白酶抑制剂(cystatin)家族中的一个亚类,在结构上与cystatin家族具有一定的同源性,但缺少胱氨酸蛋白酶抑制活性必需的保守序列,主要在睾丸及附睾中表达。探究CRES亚类的表达调控及其生物学功能将有助于阐明精子发生与成熟的分子机制,为解决精子成熟异常引起的不孕症提供分子基础,也为开发一些阻断精子成熟的男性避孕药物提供新的设计思路。     

胱蛋白酶抑制剂超家族中的新成员--CRES亚类

胱蛋白酶抑制剂超家族由stefins、cystatins及kininogens三个家族组成，CRES亚类是近年来发现的cystatins家族的新成员，主要包括Cres、Cres2、Cres3、Testatin、Cystatin T、Cystatin SC、Cystatin E1及Cystatin E2等，它们在结构上与cystatins家族具有一定的同源性，但不具备cystatins抑制半胱氨酸蛋白酶所必需的三个功能位点，主要在雄性生殖系统尤其是睾丸及附睾中表达。探究CRES亚类的表达调控及其生物学功能将有助于阐明精子发生与成熟过程的分子机制。     

American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group Survey on Chimeric Antigen Receptor T Cell Therapy Administrative,Logistic, and Toxicity Management Practices in the United States

Administration of immune effector cell (IEC) therapy is a complex endeavor requiring extensive coordination and communication of various healthcare and administrative teams. Chimeric antigen receptor (CAR) T cells are the most established IEC therapy available. As of July 2018 two commercial gene therapy products, tisagenlecleucel and axicabtagene ciloleucel, have been approved by the US Food and Drug Administration. To gain insight into the infrastructure and practices across the country, the American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group conducted an electronic survey on the current administrative, logistic, and toxicity management practices of CAR T cell therapy across the United States. This survey consists of 52 responses from institutions of varying sizes, most of which (～80%) had previous investigational experience with CAR T cell therapy. Absorbing the energy of this exciting new treatment has challenged hematopoietic cell transplant programs across the country to strengthen department infrastructure, develop new committees and policies, and implement significant education to ensure safe administration. With the variety of experience with CAR T cell therapy, we hope this survey can contribute to the existing published literature and provide support and consensus to established and developing IEC programs and practice guidelines.     

胱蛋白酶抑制剂超家族成员CRES的研究进展

胱蛋白酶抑制剂相关的附睾精子发生(cystain-related epididymal spermatogenic,CRES)蛋白是胱蛋白酶抑制剂(cystatin)家族中的一个亚类,在结构上与cystatin家族具有一定的同源性,但缺少胱氨酸蛋白酶抑制活性必需的保守序列,主要在睾丸及附睾中表达.探究CRES亚类的表达调控及其生物学功能将有助于阐明精子发生与成熟的分子机制,为解决精子成熟异常引起的不孕症提供分子基础,也为开发一些阻断精子成熟的男性避孕药物提供新的设计思路.     

CAR-T细胞治疗的神经毒性副反应处理新策略

[摘要] 嵌合型抗原受体修饰T (chimeric antigen receptor modified T,CAR-T)细胞疗法是肿瘤免疫治疗的重要手段之一,CAR-T细胞的靶向性、杀伤活性、增殖性和持久性较常规T细胞明显提高,并且经过不断的改进演变,其在血液系统肿瘤治疗中取得了巨大的成效,受到广泛的关注。然而,其治疗过程中出现的神经毒性,也称CAR-T细胞相关脑病综合征(CAR-T cell relevant encephalopathy syndrome,CRES),影响了CAR-T疗法的临床应用。探索CRES的发病机制及其高风险因素、寻找相应的处理策略,对预防和治疗CRES具有重要意义。本文以CD19-CAR-T 细胞治疗为例,就CRES的发病症状、发病机制、高风险因素及应对策略作一综述,为临床治疗提供参考。