Functional comparison of engineered CAR-T cells targeting cell surface proteins versus MHC-peptide complexes

Adoptive T cell therapies have come to be an attractive form of immunotherapy for hematologic malignancies and solid cancers. Much of the attention has focused on synthetic receptors referred to as CARs. Chimeric antigen receptors (CARs) are engineered molecules that contain the variable domains of a specific antibody, fused with transmembrane and intracellular signaling domains derived from proximal T cell signaling machinery. One limitation of current CAR T cell strategies is that they require extracellular surface targets on the tumor cells.

Our lab has developed recombinant Abs that mimic TCR specificity, termed TCR-like (TCRL) Abs. TCR-like-based CARs recognize MHC-peptide complexes on the surface of targeted cells, like TCRs. However, they have the same signaling machinery as the current CARs instead of native TCRs. Thus, these two approaches differ in the type of antigens to which they are targeted for: the common CAR-T cells target cell surface proteins while the TCRL based CAR-T cells target intracellular peptides presented on MHC complexes.

To fully exploit the therapeutic potential of CAR-T cells, the aim of our study is to compare these two forms of engineered cells, in terms of antigen sensitivity and functional properties against melanoma cells. Our CAR T cells target (1) Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP), (2) HLA-A2-Tyrosinase complex. Both MCSP and HLA-A2-Tyr are commonly expressed by melanoma cells, making them prime target antigens. While preserving similar parameters of affinity, avidity and antigen density, we plan to examine whether or not there are significant differences between these two approaches.