NIH grant: Modulating B7-H3 to improve engineered T cell therapies for cancer (1K22CA303768-01A1)

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NIH grant 1K22CA303768-01A1: Modulating B7-H3 to improve engineered T cell therapies for cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Pradip  Bajgain. Award: $190969.
Start: 2026-08-01T00:00:00.
Chimeric antigen receptors (CARs) are synthetic receptors designed to integrate the antigen specificity of an
antibody with the cytotoxic potential of effector T cells. Redirecting T cell immunity against cancer using CARs
has revolutionized the treatment of hematologic cancers like B-cell lymphoma and multiple myeloma. In contrast,
solid tumors, which account for approximately 90% of all cancers, have proven much more refractory to CAR T
therapies. Among the challenges impeding the development of successful CAR therapies for solid tumors are
the rarity and heterogeneity of tumor-associated antigens. B7-H3, a transmembrane protein overexpressed in
most solid tumor types, may provide an opportunity to overcome these challenges due to its minimal expression
in normal tissues and limited tumor heterogeneity. As a member of the B7 family of immune checkpoint proteins,
B7-H3 is known to promote tumorigenesis, partially by suppressing T cell effector function, which makes it a
relevant target for CAR therapy. Consequently, the efficacy of B7-H3-specific CARs against several B7-H3+
cancers are being investigated in preclinical and clinical studies; however, CAR T cell persistence and durable
anti-tumor activity have been reported only in a small subset of patients so far. An overlooked phenomenon
which can severely impact T cell persistence and therefore, anti-tumor efficacy is B7-H3 expression by activated
T cells. This is expected to diminish CAR T cell activity regardless of CAR specificity due to B7-H3-mediated co-
inhibition among T cells. For B7-H3 CARs, besides co-inhibition, B7-H3 induction can also result in CAR-
mediated elimination of B7-H3+ T cells through a process called fratricide. These adverse effects caused by B7-
H3 induction on T cells may contribute to the suboptimal clinical potency of CAR therapies targeting B7-H3 as
well as other solid tumor antigens. To date, effective methods to block the immunoinhibitory activity of B7-H3
have been challenged by the absence of a known receptor or validated function blocking antibodies. This study
aims to develop B7-H3 CAR therapies that are more effective against solid tumors and augment the potency of
other CAR therapies by averting the immunosuppressive effects of B7-H3. To achieve these objectives, I plan to
equip CAR T cells with novel synthetic receptors designed to disrupt B7-H3 expression and simultaneously
stimulate T cells, essentially converting the immune-inhibitory effects of B7-H3 into anti-tumor co-stimulatory
cues. This study will also increase our understanding of B7-H3 kinetics in T cells and its role in anti-tumor
immunity. These findings will facilitate future research aimed at modulating or targeting B7-H3 to enhance the
clinical efficacy of T cell therapies for cancer. This project integrates my graduate training in T cell engineering
with my postdoctoral work on B7-H3 CAR development. My long-term career objective is to establish an
independent research program aimed at improving the therapeutic outcomes of engineered T cell therapies in
patients with solid tumors. By supporting the proposed study, the K22 award will enable me to generate data for
publications and my first R01 grant application, which are important steps towards achieving my career goal.

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