CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy

Abstract

Chimeric antigen receptors (CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex (MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor (TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif (ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions.

Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy

“…26 Consistent with the reported physical incorporation of CAR elements into the endogenous TCR/CD3 complex, 35,36 we found that TCR-stimulated CAR.GD2 NKT cells exhibited a pattern of Th2-or Th1-like polarization that was nearly identical to that elicited by CAR stimulation and was again dependent on the presence of CD28 or 4-1BB endodomains in the CAR constructs (supplemental Figure 2).…”

A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia

“…For example, in a murine model, Yang et al [8] showed that TCR engagement negatively affected CD8+ CAR T-cell expansion. Similarly, Bridgeman et al [9] demonstrated that the interaction between TCR and CAR decreased CAR T-cell potential to eradicate tumor cells.…”

Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia

“…1 The CD19 antigen recognition domain is responsible for binding of the CAR T cell to CD19. CD3-z is critical for initiating T-cell activation and antitumor activity, as measured by cytotoxicity and cytokine production, 2 and the 4-1BB co-stimulatory signaling enhances proliferation, antitumor activity, oxidative metabolism, central memory differentiation, and persistence of the CTL019 cells both ex vivo and in animal models. 1,3,4 Early results from clinical studies of CTL019 in patients with CD19…”