TCR-engineered T cells in the era of CAR T cells: seeking the best of both worlds

Abstract

Receptor-edited cellular therapy of cancer has yet to fulfill its full potential. To increase the fraction of curative responses it will be crucial to increase the therapeutic breadth of cellular therapy products, both in the antigens that are targeted as well as in functionality. The ideal cellular therapeutic will target multiple antigens at a time, both HLA-dependently as well as independently of HLA. Functionally, cellular therapy needs to be efficient enough to induce sufficiently deep responses in diverse microenvironments, lesion sites and patients, while at the same time maintaining a manageable toxicity profile. The results presented within this thesis support the complementary use of TCR-engineered (eTCR) T-cell therapy together with chimeric antigen receptor (CAR) T cells to realize a multi-targeting, multi-functional product. We found that eTCR T cells are functionally different from CAR T cells, performing differently in different contexts. Furthermore, HLA-dependent and HLA-independent targeting could be leveraged to enable a broader coverage of tumor antigens to prevent antigen escape. Multi-antigen-targeting, single T-cell products using TCRs and CARs can be utilized to achieve that, but pose additional caveats.