Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010

Abstract

T cells that are genetically modified to express single-chain chimeric antigen receptors (CAR) have shown promise in early cancer immunotherapy clinical trials. Unfortunately, 2 recent deaths in cancer patients treated with CAR T cells have created some uncertainty on how to best mitigate patient risk, while continuing to advance this very promising therapeutic avenue. In order to address these concerns, the Recombinant DNA Advisory Committee (RAC) held a symposium, the objectives of which were to first review the reported treatment-associated toxicities and, second, to discuss methods for improving safety and efficacy. This report highlights the issues raised as part of this discussion, with a specific focus on protocols infusing CAR T cells. Because this was not a consensus conference, the opinions described should not be construed to represent those of any individual RAC member, the RAC as a body, conference participants, the National Institutes of Health, or the U.S. Food and Drug Administration.

Figure 1. Evolution of CAR-T cell Design

A. Initial CAR-T cells were composed of an antigen specific scFv linked to the TCR zeta chain. These CARs were expressed in non-clonal T cell populations with diverse specificities of their endogenous TCRs. B. In subsequent strategies, investigators have attempted to prolong gene-modified T cell survival by expressing 1^st generation CARs in T cells whose endogenous TCRs recognize specific antigens of persisting viruses, e.g. EBV, allowing for the induction of the costimulatory cascade upon cognate TCR ligation. C. Because of difficulty isolating TA-specific T cells from most types of solid tumors, other investigators have employed a modified CAR design in which the 4-1BB/CD28 intracellular signaling domains are linked to the transmembrane region. In these CARs, scFv antigen recognition results in T cell activation through the TCR zeta chain leading to prolonged survival secondary to appropriate costimulation.