Ali Zamat

BME PhD Proposal Presentation

Date: 2023-07-11
Time: 10:00am - 12:00pm
Location / Meeting Link: Marcus Nanotechnology Building Room 1116 / https://gatech.zoom.us/j/6841027233?pwd=LzFSbU9oM045bkMzVCtXZDRwcnFBZz09

Committee Members:
Gabe Kwong, PhD (Advisor); Costas Arvanitis, PhD; Susan Thomas, PhD; John Blazeck, PhD; Sarwish Rafiq, PhD


Title: Thermal control of CAR T cells to treat heterogenous tumors and enhance systemic antitumor immunity

Abstract:
Chimeric antigen receptor (CAR) T cell therapies are transforming clinical care of hematological malignancies; however, they have shown limited clinical success in treating solid tumors. Numerous efforts are underway to expand the use of CAR T cells for different cancer types, but their effectiveness in treating solid tumors have been limited by the fact that solid tumors are heterogenous; targeting a single antigen using CAR T cells typically result in tumor antigen escape, leading to relapse of the disease. Potent immunomodulators such as bispecific T cell engagers (BTEs) are being investigated for their ability to direct T cell cytotoxicity towards solid tumors. However, these biologics typically suffer from short half-lives and systemic toxicity – thus requiring continuous infusion or sub-par dosing regimens to administer safely. My thesis seeks to develop spatially targeted drug delivery using thermal sensitive CAR T cells to overcome hurdles associated with conventional treatment of heterogenous solid tumors. In contrast to conventional drug delivery mechanisms that rely on passive diffusion to deliver cargo to tumors, immune cells penetrate and infiltrate deep within tumors. This active mechanism of cell transport provides unique opportunities to engineer T cells both as a therapy and as a delivery vehicle. In this thesis proposal, we will develop a new strategy whereby bispecific T cell engagers (BTEs) will be delivered with spatial precision upon focused ultrasound (FUS) mediated activation of thermal sensitive CAR T cells in heterogenous tumors. This approach is expected to significantly enhance local CAR T cell activity by mitigating tumor antigen escape, while potentiating systemic antitumor immunity by priming the endogenous immune system against antigen-negative tumor cells. We will implement thermal gene switches (TS) for heat-triggered control of transgene expression in primary human and murine T cells. TS constructs are transcriptionally silent at body temperature (37°C) but after exposure to a short duration of heat (10 min. at 40–42°C), express transgenes to levels greater than 200-fold above basal levels. FUS will provide the ability to noninvasively deposit heat with spatial precision regardless of depth in the body with volumetric spatial and real-time temperature profiles. These studies will focus on BTEs targeting Natural killer group 2, member D ligands (NKG2DL), which are stress-induced antigens highly expressed on tumor cells as well as on immunosuppressive cells. Validations were first performed in xenograft models of heterogenous flank tumors irradiated with established NIR-mediated photothermal heating protocols to assess the impact of local BTE production by CAR T cell to mitigate antigen escape (Aim 1). We will then implement our system in models of breast cancer brain metastasis (BCBM) by magnetic resonance imaging guided focused ultrasound (MRgFUS) for transcranial activation of intratumoral CAR T cells (Aim 2). Finally, we will engineer murine NKG2D BTEs to assess the impact of local treatment on endogenous immunity by implementing fully immunocompetent, syngeneic mouse models of breast cancer (Aim 3). Successful completion of these aims may improve the efficacy of T cell therapies against refractory disease and improve systemic antitumor responses.