Designing better T cell epitopes for improved T cell vaccines and therapies

Abstract The most important feature of antigenic peptides that stimulate potent T cell responses during vaccination or adoptive T cell therapies is their ability to bind and stabilize Major Histocompatibility Complex (MHC) mole- cules. Decreasing T cell receptor (TCR) signaling in response to cognate epitope/MHC programs functionally distinct pools of memory CD8+ T cells. This proposal builds on the very unexpected finding that specific sets of T cell epitopes promote the induction of functionally superior memory CD8+ T cells exhibiting higher fitness and stem cell-like properties. Memory T cells with stem cell-like features maintain greater progeny potential, have higher self-renewal, survival and clonal expansion capacities. They are considered at the apex of memory cells and the most ideal subset of memory CD8+ T cells for effective responses against tumors and chronic infec- tions. In this proposal, we hypothesize that the mode of TCR interaction with its cognate antigenic peptide de- termines the fate of naïve T cells during priming. We will use molecular dynamic simulation coupled to func- tional in vitro and in vivo assays to define and validate the key molecular and TCR/epitope interacting features that promote the differentiation of stem-cell like memory CD8+ T cells. We propose to develop an algorithm for the identification and design of such T stem-cell skewing epitopes. Overall, the work will provide an innovative framework on how to best design antigenic peptides that favor the acquisition of stem cell-like properties by memory T cells. The project has the potential to directly impact the longevity and functional efficacy of i) vac- cine-induced memory T cells, and ii) adoptively transferred T cells (both Chimeric Antigen Receptor (CAR) and non-CAR) in the context of life-threatening chronic infections and cancers.