Wednesday, February 5, 2025
2/5/2025
Project Summary 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 results in tumor antigen escape, leading to relapse of the disease. Although systemic delivery of immunomodulators can potentiate anti-tumor responses, it can also lead to debilitating adverse events from on- target, off-tumor toxicity, cytokine release syndrome, and in some cases, life-threatening autoimmunity. By contrast, intratumoral administration of immunomodulators has been shown to reduce systemic exposure while improving efficacy of systemic therapies. Immunity against tumor antigens, resultant of epitope spreading after tumor cell killing, leads to a diversification of epitope specificity from the initial epitope – priming the endogenous immune system against larger pool of targets. This proposal seeks to use thermal sensitive CAR T cells, which traffic and infiltrate deep within tumors, to intratumorally produce bispecific T cell engagers (BTEs) and induce epitope spread by DC priming of endogenous anti-tumor T cells to develop robust immunity. Focused ultrasound (FUS) will be used to spatially deposit heat within heterogenous tumors and activate CAR T cells engineered with a thermal gene switch (TS) which allows for heat-triggered control of transgene expression in 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. 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. Preclinical evaluation will be performed in murine models of breast cancer in fully immunocompetent mice. This approach is expected to significantly enhance local CAR T cell activity against heterogenous tumors, while potentiating endogenous antitumor immunity. To assess this, epitope spread by DC mediated priming of the endogenous T cells will be investigated. Successful completion of the aims of this study is expected to elucidate mechanisms by which local BTE secretion by CAR T cells can prime endogenous T cell immunity.
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