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)