TCR Targeting Antibodies for the Treatment of T cell Cancers

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Project Summary Antibody-mediated targeted immunotherapies are highly effective in killing cancer cells. T cell leukemias and lymphomas, collectively known as T cell cancers, affect ~100,000 patients worldwide each year. Relapsed T cell cancers respond poorly to aggressive chemotherapy with a 5-year survival between 7% to 38%. Thus, T cell cancers particularly warrant antibody-mediated targeted immunotherapy to improve patient outcomes. However, developing a T cell cancer targeting immunotherapy is challenging as the immunotherapy will have to preserve enough healthy T cells to maintain a functioning immune system. T cells express the T cell receptor (TCR) on the cell-surface. Although all T cells express TCR, they can be distinguished based on the TCR beta chain constant region (TRBC) which is derived from one of two gene segments, TRBC1 or TRBC2. I led a team that demonstrated that in healthy T cell populations, about 45% of cells express TRBC1 while the other 55% express TRBC2. However, clonal T cell cancers express either TRBC1 or TRBC2 (Paul et al., Sci. Transl. Med. 2021). Thus, I hypothesize that antibody-mediated specific TRBC1 or TRBC2 targeting will eradicate the clonal T cell cancers while preserving half of the healthy polyclonal T cell population. I also developed a TRBC1- targeting bispecific antibody (αTRBC1) that selectively kills TRBC1+ T cell cancers (and TRBC1+ healthy T cells) while preserving the healthy TRBC2+ T cells in vitro. These in vitro observations will require confirmation in animal models before initiation of future human clinical trials. For Aim 1, I will determine the in vivo activity of the αTRBC1 bispecific antibody. I will test the ability of αTRBC1 antibodies to induce tumor regression in multiple mouse models of T cell cancers. I will then examine if the remaining healthy TRBC2+ T cells retain all of the immune cell subsets required for a functioning immune system. I will also test if therapeutic pressure from the αTRBC1 bispecific antibody will give rise to a low TCR expressing T cell population that will be resistant to therapy. For Aim 2, I will test feasibility of TRBC2-targeting on T cell cancers. As a TRBC2-targeting antibody is currently unavailable, I will use phage display to develop TRBC2-specific antibodies. I will then test the cytotoxicity of TRBC2 targeting antibodies in vitro and in multiple mouse models of T cell cancers. Our TRBC- directed antibodies will fill an unmet need for the treatment of T cell cancer patients. The proposed in vivo and mechanistic studies will provide the pre-clinical validation required for the initiation of an early-phase human clinical trials that will test the safety and efficacy of TRBC1- and TRBC2-targeting antibodies. My long-term goal is to become an independent laboratory-based physician-scientist focusing on developing novel therapeutic approaches for T cell cancers. Through this proposal, I will also acquire the research skills and career experience needed to reach this goal. These skills will be critical to the development of a relevant, impactful translational research program in human T cell leukemias and lymphomas.