Chimeric antigen receptor transduced T cells: Tuning up for the next generation

Abstract

Chimeric antigen receptor (CAR) T cell therapy has recently achieved impressive clinical outcome in patients with CD19-positive hematologic malignancies. Extrapolation of CAR T cell treatment to solid tumors, however, has not yet yielded similar results. This might be due to intrinsic causes, e.g. insufficient CAR T cell activation or CAR toxicity as well as extrinsic factors displaying an unfavorable tumor environment for CAR T cells by raising physical and chemical barriers. In this review, we discuss the advantages as well as major obstacles of CAR T cell therapy, particularly in the context of solid tumors, and focus on efforts and novel strategies in CAR T cell development.

Idelalisib for optimized CD19‐specific chimeric antigen receptor T cells in chronic lymphocytic leukemia patients

“…Apart from the spacer, the intracellular domains play an important role in CART cell functionality and vector design evolved in the last decades. 2 First CAR vectors contained only a CD3ζ-chain domain, whereas the second generation (2G) and 3G have been developed using or combining costimulatory domains such as CD28, 4-1BB (CD137) and/or OX40 (CD134). 43,44 It is known that CD28 supports stronger T cell expansion and enhanced tumor eradication whereas activity of 4-1BB is linked to longer persistence and reduced risk of relapse.…”

“…The remarkable results of anti‐CD19 chimeric antigen receptor T (CART) cell therapy sparked new hope for relapsed or refractory patients with B cell malignancies . However, full antitumor activity for complete cancer eradication can be insufficient . Efficacy of CART cell therapy is associated with in vivo proliferative capacity and sustained persistence of the gene‐modified cells .…”

“…1 However, full antitumor activity for complete cancer eradication can be insufficient. 2 Efficacy of CART cell therapy is associated with in vivo proliferative capacity and sustained persistence of the genemodified cells. 3 Thereby, transfer of defined T cell phenotypes can influence antitumor activity.…”

Lipid-mediated insertion of Toll-like receptor (TLR) ligands for facile immune cell engineering

“…In 2017, the FDA approved 2 adoptive T-cell immunotherapies using chimeric antigen receptors (CARs) for treating cancer, with hundreds of other T-cell therapies currently in clinical trials in cancer and other chronic diseases (46). The addition of more co-stimulatory signals, other adjuvants, or signaling domains to CARs by genetic additions has become an increasing trend in the field (47)(48)(49). However, the uncontrolled release of genetically encoded inflammatory cytokines or other adjuvants from perpetually activated CAR T cells presents a new challenge for toxicity management: lack of dose control (45,50).…”

Transmembrane domain-mediated Lck association underlies bystander and costimulatory ICOS signaling

“…33 Much effort has been made to optimize CARs to function more efficiently, and cytoplasmic signaling motifs from various immune molecules are important building blocks in the CAR-engineering toolbox. 34 Given the Lck-associating nature of the ICOS TMD, we replaced the CD8 transmembrane domain in the standard CD19reactive FMC63-BBz CAR (BBz CAR) with the ICOS TMD (ICOSTM-BBz CAR) and tested the two types of receptors in Jurkat cells. As shown in Fig.…”