We harness the power of engineering to steer immune responses
A number of issues are associated with adoptive T cell therapy, such as functional exhaustion, dysregulated metabolism, and poor in vivo persistence which could benefit from an effective vaccine.
Building on the synthetic amphiphile vaccine platform we recently developed for CAR T cells, we aim to elucidate the optimal design rules of this synthetic vaccine. This project will leverage high-throughput library screening, genomics and chemistry to dissect immune cell crosstalk at the single-cell level and its impact on vaccination outcomes.
This project will guide the design of a robust major histocompatibility complex (MHC)-independent vaccination strategy applicable to any adoptive T cell therapy(e.g., CAR T, Treg, and TIL therapy), potentially redefining therapeutic T cell vaccination.
We are also interested in engineering immune cells using surface chemistry to achieve spatial-temporal modulation of their activities and functionalities.
Targeting malignant cells via cell surface antigens using CAR T therapy has proven highly effective in controlling certain blood cancers. However, loss of surface antigen became one of the major mechanisms of resistance to CAR T therapy, and many solid tumors often do not possess unique surface antigens, making it challenging to generalize cellular immunotherapy via this surface antigen-based tumor-targeting mechanism.
An alternative and complementary strategy could be engineering therapeutic cells to specifically sense and respond to features associated with the tumor microenvironment (TME).
This project will employ multi-omics, synthetic biology, and viral engineering to define and create genetic circuits enabling immune cells to distinguish tumor from normal tissue.
Therapeutic applications of highly potent immune-modulatory proteins, such as cytokines, often need to overcome two major hurdles, specificity and toxicity. Our recent work on matrix-anchoring fusion cytokines (e.g., Lumican-IL12) presents an alternative strategy via sustained local release within the tumor microenvironment, thereby preventing leakage into circulation.
Along this line, we aim to harness protein fusions, directed evolution and chemical modification to engineer proteins with desired trafficking profile, release kinetics, enhanced or completely new functions for immunotherapy in situ or as therapeutic payload for engineered cells.