Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment

Protein & Cell, May 2017

Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation.

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Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment

Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment Zhenguang Wang 0 Yelei Guo 0 Weidong Han 0 0 Molecular & Immunological Department, Bio-therapeutic Department, Chinese PLA General Hospital , Beijing 100853, China Received December 28, 2016 Accepted March 15, 2017 Chimeric antigen receptor (CAR) is a recombinant immunoreceptor combining an antibody-derived targeting fragment with signaling domains capable of activating cells, which endows T cells with the ability to recognize tumor-associated surface antigens independent of the expression of major histocompatibility complex (MHC) molecules. Recent early-phase clinical trials of CAR-modified T (CAR-T) cells for relapsed or refractory B cell malignancies have demonstrated promising results (that is, anti-CD19 CAR-T in B cell acute lymphoblastic leukemia (B-ALL)). Given this success, broadening the clinical experience of CAR-T cell therapy beyond hematological malignancies has been actively investigated. Here we discuss the basic design of CAR and review the clinical results from the studies of CAR-T cells in B cell leukemia and lymphoma, and several solid tumors. We additionally discuss the major challenges in the further development and strategies for increasing anti-tumor activity and safety, as well as for successful commercial translation. chimeric antigen receptor; CAR-T; engineered T cells; adoptive cell therapy; cancer treatment INTRODUCTION “Natural forces within us are the true healers of disease.”—Hippocrates (de Coana et al., 2015). Undoubtedly, the immune system is the right cancer healer, especially in the context of currently available therapies such as chemotherapy, radiotherapy, and targeted therapy, which have been less successful than anticipated. Harnessing the immune system to kill cancer is a durable concept that has more than 100 years of history; it was first demonstrated in 1891 by William Coley’s use of Coley’s toxin, a mixture of heat-killed bacteria to elicit regression of inoperable sarcomas (Elert, 2013). Despite this early beginning, efforts to reliably manipulate the immune system to promote tumor regression have been universally disappointing. In recent decades, with the significant progress in understanding the inherent immune biology related to cancer, effective immunotherapy treatments for cancer have gradually emerged (Fyfe et al., 1995; Atkins et al., 1999; Kantoff et al., 2010) and reached an important turnover in the history of cancer treatment as named by Science magazine the “breakthrough of 2013” due to the striking proof-of-concept data of immune checkpoint anti-CTLA-4 and PD-1 antibodies as well as CAR therapy (Couzin-Frankel, 2013). Subsequently, a spectrum of encouraging outcomes of those modalities in other tumors have attracted more big players during the past 2 years, denoting that cancer immunotherapy is coming of age. The presented concept of CAR is based on two seminal research studies as the increasing understanding of the construct and function of T cell receptor (TCR) complex (Fig. 1). First, in 1989 Gross et al. constructed a chimeric TCR (cTCR) gene made by replacing the Vα and Vβ extracellular domains of the TCR chains with their VH and VL immunoglobulin homologs (CαVH + CβVL or CαVL + CβVH). The resulting cTCR was expressed on the surface of cytotoxic T lymphocytes, recognized antigen in a non-MHC-restricted manner, and effectively transmitted the transmembrane signal for Tcell activation (Gross et al., 1989). These results proved that replacing the variable region of TCR with those of antibody for endowing the T cells with antibody-type specificity is viable (Eshhar, 2014), and was subsequently followed by Goverman CD25 CD4 CD8α δ ε ε C L C L Hinge TM Co-stimulatory IgG1 CD4 CD28 CD137 IgG1 CD28 CD137 C R et al. with a consistent outcome (Goverman et al., 1990). Another pioneering study mainly focused on the chimeric proteins constructed between either CD8, CD4, or CD25 (also called α chain of the human interleukin-2 receptor) and cytoplasmic tails of ζ (Irving and Weiss, 1991; Romeo and Seed, 1991; Letourneur and Klausner, 1991). Those chimeric proteins have resulted in biochemical events of early T cell activation such as interleukin-2 (IL-2) production and Ca2+ influx, which validated that cytoplasmic tails of ζ could replicate much of the TCR signaling (van der Stegen et al., 2015). Taking advantage of these advances, in 1993 Eshhar et al. pioneered to design a gene composed of a single chain variable fragment (scFv) of an antibody linked with ζ chains, which is aimed to overcome the difficulty in activating anti-tumor T cells through the TCR (Eshhar et al., 1993). The transfected cytolytic T cell hybridoma triggered IL-2 secretion upon encountering antigen and mediated non-MHC-restricted hapten-specific target cell lysis. This new artificial receptor called T-body is known as the first-generation CAR. Subsequent experiments after t (...truncated)


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Zhenguang Wang, Yelei Guo, Weidong Han. Current status and perspectives of chimeric antigen receptor modified T cells for cancer treatment, Protein & Cell, 2017, pp. 1-30, DOI: 10.1007/s13238-017-0400-z