Zizhen (Jane) Zha
BME PhD Proposal Presentation

Date: 2026-08-20
Time: 2:00 - 4:00 PM
Location / Meeting Link: U.A. Whitaker 1214

Committee Members:
Gabriel A. Kwong (Advisor); Stanislav Emelianov; Cheng Zhu; John Blazeck; Nicole Schmitt


Title: Thermally regulated anchored payloads for CAR T cell therapy against solid tumors

Abstract:
Engineered cell therapies are living drugs that have transformed the field of cancer immunotherapy, with seven currently Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cell therapies for hematological cancers. However, CAR T cells alone are not sufficient for treating solid tumors, due to reasons including immunosuppressive microenvironment and single-antigen recognition. Strategies such as proinflammatory cytokines and cancer vaccines have been used to enhance CAR T cell therapies to overcome suppression and expand the tumor recognition. To fully take advantage of these strategies, the drug payloads require efficient delivery and retention at tumors or draining lymph nodes. Engineering drug payloads with tumor-binding domains, as used in antibody drug conjugates, enhances the localization, but systemic delivery suffers from insufficient delivery into tumors and draining lymph nodes due to various physiological binding site barriers, such as vasculature, stromal and target barriers. This highlights the need for a platform with spatiotemporal control of drug deposition as well as its retention within tumors and draining lymph nodes to effectively enhance CAR T cell therapies against solid tumors. Our lab has previously developed an ultracompact thermal bioswitch (TS) that allows remote control of payload production directly within tumor. In addition, nanobodies (VHH) have been widely used to anchor payloads to desired sites due to their compact size, stability, and high binding affinity. In this thesis proposal, we will develop a thermally regulated anchored payload (TRAP) fusion protein platform, in which CAR T cells are engineered to express nanobody conjugates that bind tumor or draining lymph node antigens under TS control. With local tumor hyperthermia, TRAP fusion protein is expected to bypass the systemic delivery barrier and directly deposit drug payload within tumor from infiltrating CAR T cells. We will equip TRAP with either tumor-anchoring and lymph node-anchoring VHH to enable retention at site of production within tumor or retention at draining lymph nodes following the natural lymphatic drainage. This strategy is expected to increase the effective local concentration of payloads while minimizing systemic exposure. We will first optimize TRAP protein design for high binding affinity while maintaining bioactivity of IL-12. We will then evaluate the safety and efficacy of TRAP-12 CAR T cell therapy in tumor-bearing mice (Aim 1). Building on this platform, we will apply optimized TRAP design to deliver neoantigen peptides to draining lymph nodes. We will first validate the anchoring towards lymph nodes, as well as assess the efficacy of TRAP-peptide construct to activate and expand antigen specific T cells. We will then evaluate the efficiency of expanding neoantigen-specific T cell populations and efficacy of TRAP-neoantigen-peptide CAR T cells (Aim 2). Successful completion of these studies will establish a platform for remote spatiotemporally controlled drug payloads for enhancing CAR T cell therapies against solid tumors.