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.