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Modulating B7-H3 to improve engineered T cell therapies for cancer

Award Number: K22CA303768
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Modulating B7-H3 to improve engineered T cell therapies for cancer - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $190,969 )
2026	2026	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	1	7/21/2026	NEW	$190,969
														Subtotal = $190,969

Grand Total All Awards = $190,969

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Modulating B7-H3 to improve engineered T cell therapies for cancer

Award Number: K22CA303768

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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