Research ArticleCancer

TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance

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Science Translational Medicine  22 Nov 2017:
Vol. 9, Issue 417, eaag1209
DOI: 10.1126/scitranslmed.aag1209

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A tale of two receptors

Although there has been an explosion of research on chimeric antigen receptor (CAR) T cell therapy, most preclinical studies use transduced human T cells in immunodeficient mice so that the clinical products can be evaluated. However, the endogenous T cell receptors (TCRs) on the human cells are unable to be activated by peptides presented in mouse MHC. To determine how CAR activity is affected by TCR engagement, Yang et al. used a CAR targeting CD19 and multiple types of transgenic T cells in immunocompetent mice. Exposure of CD8 CAR T cells to the antigen recognized by the TCR led to T cell exhaustion, apoptosis, and lack of efficacy; this phenomenon was not observed for CD4 CAR T cells. Their findings demonstrate how considering T cell biology could further improve CAR T cell therapy.

Abstract

Chimeric antigen receptor (CAR)–expressing T cells induce durable remissions in patients with relapsed/refractory B cell malignancies. CARs are synthetic constructs that, when introduced into mature T cells, confer a second, non–major histocompatibility complex–restricted specificity in addition to the endogenous T cell receptor (TCR). The implications of TCR activation on CAR T cell efficacy has not been well defined. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T cell therapy for pre–B cell acute lymphoblastic leukemia in which the CAR is introduced into T cells with known TCR specificity, we demonstrate loss of CD8 CAR T cell efficacy associated with T cell exhaustion and apoptosis when TCR antigen is present. CD4 CAR T cells demonstrate equivalent cytotoxicity to CD8 CAR T cells and, in contrast, retain in vivo efficacy despite TCR stimulation. Gene expression profiles confirm increased exhaustion and apoptosis of CD8 CAR T cells upon dual receptor stimulation compared to CD4 CAR T cells and indicate inherent differences between CD4 and CD8 CAR T cells in the use of T cell–associated signaling pathways. These results provide insights into important aspects of CAR T cell immune biology and indicate opportunities to rationally design CAR constructs to optimize clinical efficacy.

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