Fig. 1. Neoepitope generation and targeting.

Conventional TCRs can recognize cognate pMHC complexes, but there is a need for further co-stimulatory signaling to fully activate T cells. When a mutation occurs in the tumor antigen, the previous tumor epitope-reacting TCRs have no/low affinity to the generated neoepitope. In order to recognize the neoepitope/MHC complex, the variable region of TCR undergoes affinity maturation process, and further TCR clonal selection is occurred. Neoepitope-reactive TCR variable domains (TCRv) can be further used in CAR structure. Although CAR T cells (here a 3rd generation CAR) are rapidly and strongly activated when stimulated by the target antigen, they can only target cell membrane surface proteins which are ~1% of total proteins expressed in the cell. Therefore, CARs are unable to target neoepitopes in the context of major histocompatibility complex (MHC) molecules. However, TCR-like CARs (with a scFv targeting pMHC) or TCR-CARs (with a TCRv targeting pMHC) can be developed to have the advantages of both TCRs (for targeting neoepitopes) and CARs (for rapid and robust activation).