Next-generation T cell therapy: SMARTER T cells for enhanced and durable anti-tumor immunity

PROJECT SUMMARY/ABSTRACT Recently, remarkable progress has been made in cancer treatment employing adoptive cell transfer (ACT) of tumor-specific “killer”, CD8+ T cells. Various engineered T cells including chimeric antigen receptor T (CAR-T) cells, have shown great potential as new forms of cancer therapies. However, a hostile tumor microenvironment (TME) impedes T cell infiltration and survival and induces T cell dysfunction (i.e., ‘exhaustion’), making the beneficial effects of the therapy transient. Exhausted T cells (TEX) arise when T cells are stimulated by antigen for prolonged periods, which drives a defined differentiation process involving major transcriptional and epigenetic changes in T cells. Thus, there have been attempts to promote intratumoral T cell trafficking/proliferation but challenges with poor long-term survival and efficacy of adoptively transferred T cells in solid tumors still remain. Therefore, the goal of this proposal is to engineer T cells that better infiltrate and survive inside tumors to provide robust, durable anti-tumor T cell immunity. By combining (1) the expertise of the Dr. Kaech lab in effector and memory T cell development, (2) that of the Dr. Wang lab in integrative analysis of epigenomic/genomic data, and (3) that of Dr. Chung in protein engineering, this research will provide novel solution to the current limitation in ACT. Preliminary research generated epigenetic and transcriptional atlas of CD8+T cells and analyzed the transcription factor networks of the most tumoricidal, tumor-infiltrating “effector” T cell state, the long-lasting “resident-memory” T cell state and dysfunctional “exhausted” T cell state. Based on the understanding of T cell differentiation states, this proposal aims to design key transcription factor programs that drive desired T cell states and devise new methodologies to redirect T cell exhaustion state to toggle desirable effector and memory states and to temporally and combinatorically control the cell-state specific TFs of the adoptively transferred T cells in situ. This new class of T cell engineering platform is termed SMARTER (Specific Modifiers Assisted Reprogramming of T cell Engineered with Regulability). To generate SMARTER T cells, in Aim 1, a new platform will be devised to systemically identify novel cell-state-specific transcription factors. In Aim 2, synthetic machinery will be developed to rewire exhaustion signals to specific differentiation program. Lastly, in Aim 3, a clinically useable synthetic biology methods will be developed to enable temporal and combinatorial control of the cell- state-specific modifiers. This SMARTER platform will effectively transform T cells into “intelligent and tenacious soldiers”. These enhanced T cells will not only effectively infiltrate and kill cancer cells, but also retain the immunological memory of their “foes” and reside long-term at the tumor site, leading to complete remission.