Engineering better chimeric antigen receptor T cells

Abstract

CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

TOX as a potential target for immunotherapy in lymphocytic malignancies

“…How to convert exhausted T cells into active T cells is a problem that many scientists are trying to solve. In hematological malignancies, CAR-T cell therapy has impressive therapeutic efficacy [ 52 ]; however, it also faces the drawback that CAR-T cells lose their effects due to rapid exhaustion after injection into patients [ 37 , 52 ]. On this issue, TOX might be used as a specific target to reverse T cell exhaustion by reducing its expression activity, which can maintain the effects of CAR-T cells in patients for a longer period of time.…”

“…T cell exhaustion is a term used to describe T cells under chronic antigen stimulation that alter or lose their effector function, and this is related to abnormal expression of immune checkpoint proteins in T cells [ 35 – 37 ]. Recently, many studies have shown that TOX is a crucial transcription factor involved in exhaustion of CD8+ T cells [ 1 , 2 , 4 , 32 , 38 – 41 ].…”

Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond

“…CAR-T therapy can be broadly grouped into three groups: single-target, multi-target, and universal CAR-T (Table 2 ). The ideal therapeutic CAR-T targets a cell surface antigen that is preferentially, and ideally exclusively, expressed on myeloma cells [ 37 ]. Resistance mechanisms such as “on target off tumor” recognition (expression of targeted antigens on normal cells) and “antigen escape” (loss of targeted antigens on tumor cells) pose ongoing therapeutic challenges in CAR-T therapy [ 38 ].…”

Novel strategies for immuno-oncology breakthroughs with cell therapy

“…Cancer immunotherapy has been a game changer in cancer treatment since the approval of the immune checkpoint inhibitor (ICI), ipilimumab, in 2011 and subsequent anti-PD-1 antibody, pembrolizumab and nivolumab in 2014 [ 1 – 5 ]. Currently, 10 immune checkpoint inhibitors and 5 chimeric antigen receptor T cell (CAR-T) products have been approved in treating 17 types of malignant diseases and two tissue-agnostic indications across the world [ 6 – 12 ]. CD19-targeted CAR-T cell therapy for B cell neoplasms has opened up a new era in synthetic cancer immunotherapy [ 13 – 15 ].…”