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Development of a Surgical Drug Delivery System for Enhancement of CAR T Cell Activity

Award Number: F30CA257566
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/09/2021
PERIOD OF PERFORMANCE END DATE: 09/08/2025

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Development of a Surgical Drug Delivery System for Enhancement of CAR T Cell Activity - Project Summary and Abstract Chimeric antigen receptor (CAR) T cells are genetically engineered T lymphocytes designed to sense antigens and mount an immune response. Though CAR T cells have received FDA approval for the treatment of several hematologic malignancies, success in solid tumors is limited by a lack of specific antigens, the immunosuppressive tumor microenvironment, and treatment-limiting adverse effects such as on-target, off-tumor toxicity and cytokine release syndrome. Though investigators report strategies for mitigating these limitations such as biomaterials for reshaping the tumor microenvironment, and logic-gated CAR T cells to prevent non- specific toxicity, no proposed strategy has overcome each of these barriers. To surmount these limitations, I propose the use of a novel surgical mesh for implantation into the tumor resection cavity. This mesh will be used in conjunction with a split CAR T cell called a zipCAR, which uses a detached adaptor protein (a “zipFv”) to sense antigens. The mesh is composed of polymeric nanofibers with a matrix of chitosan deposited within the pores. The mesh supplies the zipFv adaptor protein, cytokines (IL-15), and T cell stimulatory antibodies (α- CD3/28). I hypothesize that the use of this surgical mesh will overcome the barriers to CAR T cell therapy in solid tumors by: (1) opposing T cell anergy and promoting proliferation in the resection cavity, (2) preventing antigen escape via encapsulation of zipFvs targeting multiple antigens, and (3) imparting spatiotemporal control over CAR T cell activity. Aim 1 of this proposal demonstrates the proliferation advantage of the mesh by monitoring CAR T cell proliferation in a murine model of HER2+ breast cancer. Aim 2 of this proposal demonstrates the efficacy and safety advantages of the meshes in a model of operative debulking of ovarian cancer. To demonstrate prevention of antigen escape, ROR1- and HER2-deficient OVCAR3 cell lines will be created using CRISPR-Cas9 knockouts. In a murine model of antigen escape, these cells will be used to demonstrate superior efficacy in mice treated with zipCAR T cells and meshes loaded with zipFvs against both antigens. To demonstrate superior safety, meshes will be utilized in the same model of ovarian cancer with mice that are irradiated to upregulate ROR1 expression in non-hematopoietic stem cells in the bone marrow and spleen, allowing observation of on-target, off-tumor toxicity. This proposal builds around four key components of critical research and clinical skills to support my development into an independent physician scientist: (1) an interdisciplinary research project focusing on novel surgical biomaterials for enhancement of CAR T cell activity; (2) multi-disciplinary mentoring from Drs. Grinstaff (biomaterials), Wong (immunotherapy); and, Colson (clinical medicine, animal models, and immunology), (3) academic physician scientist training in research conduct and communication skills, (4) commitment to an individual development plan (IDP) to guide my training goals.


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: 2024 ( Subtotal = $53,974 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Dietary Supplement Research Program	000	4	7/24/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Dietary Supplement Research Program	000	3	8/7/2023	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Dietary Supplement Research Program	001	2	8/22/2022	NON-COMPETING CONTINUATION	$51,752
2022	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Dietary Supplement Research Program	000	1	11/5/2021	NEW	$0
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Dietary Supplement Research Program	000	1	9/9/2021	NEW	$51,036
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Dietary Supplement Research Program	001	1	9/9/2021	NEW	$0
														Subtotal = $51,036

Grand Total All Awards = $209,456

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Development of a Surgical Drug Delivery System for Enhancement of CAR T Cell Activity

Award Number: F30CA257566

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/09/2021

PERIOD OF PERFORMANCE END DATE: 09/08/2025

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