GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade

Abstract

Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients.

Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains

“…[28][29][30][31][32] The AICD that CAR T cells exhibited in our experiments was likely There was a total of ten mice in each group except the SP6-CD828Z group, which had five mice. The graphs show the mean tumor size ± SEM for each time point.…”

“…6,27 The hinge and transmembrane regions of a CAR can potentially be important to the function of T cells expressing the CAR. [27][28][29][30] Activation-induced cell death (AICD) is a process by which T cell activation leads to apoptosis of T cells. [28][29][30][31][32] To investigate how CAR hinge and transmembrane components affect the biology of anti-CD19 CAR T cells, we have conducted experiments with CARs containing hinge and transmembrane regions from either the human CD28 molecule or the human CD8a molecule.…”

Attack of the killer clones

“…The CAR T cells have struggled to thrive and multiply inside the body, says Brown. In only one of the six patients did the engineered T cells persist beyond four months 3 . At the University of California, San Diego, Cohen, along with oncologist Thomas Kipps and colleagues, is focusing on a receptor protein called ROR1 that is expressed in many aggressive, difficult-to-treat cancers.…”

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

“…9,10 In solid tumors, however, there are concerns that retargeted T cells may be unable to overcome established tumor tolerance. 11,12 In this study, we investigate adoptive cell therapy using hTERT-specific TCRs from CD4 C Th cells. These TCRs recognize antigen in the context of HLA class II.…”