Wednesday, December 17, 2025 12/17/2025

Re-purposing Oncolytic Virotherapy to Re-invigorate CAR T Cell Therapy for Solid Tumors.

Award Number: R01CA269384
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Re-purposing Oncolytic Virotherapy to Re-invigorate CAR T Cell Therapy for Solid Tumors. - PROJECT SUMMARY Efficacy of CAR T cell therapies against solid tumors has been limited by a lack of expansion in vivo, low levels of tumor trafficking, poor functionality/persistence and by suppression in the tumor micro-environment (TME). Conventionally prepared CAR T cells are unable to retain sufficient differentiational plasticity to undergo natural pathways of T cell proliferation/differentiation/persistence in vivo for sustained, effective cytotoxic anti-tumor activity. Oncolytic viruses (OV) selectively replicate in tumor cells to generate a highly inflammatory TME which may enhance CAR T cell recruitment to, and function within, solid tumors. Our goal is to develop a novel regimen by which oncolytic virotherapy can be used as a potent immunological adjuvant to improve the efficacy of CAR T cell therapy against solid tumors. By loading the OV on the CAR T cells ex vivo, we achieved highly significant improvements in tumor therapy compared to virus or CAR T cells alone. Mice treated with completely systemically delivered CAR T and VSV developed a population of CD8+ CAR T cells with T Cell Receptor (TCR) specificity for the immunodominant H2Kb VSV N52-59 epitope of VSV which selectively expanded in vivo to very high frequency. This population of dual-specific (DS) (virus-specific and CAR T antigen-specific) memory-like (TM) CAR T cells 1). persisted in mice for much longer than conventional CAR T, 2). was significantly more functional against tumor, and 3). could be rapidly re-activated in vivo against tumor by a secondary systemic boost with homologous virus, resulting in long-term tumor cures. These therapeutic effects were observed with two different OV (VSV and reovirus) and across tumor sites (subcutaneous and intra-cranial). Therefore, here we propose a completely novel approach to expand the scope of CAR T cell therapy against solid tumors in which dual specific CAR T cells with improved activity against tumors are generated by using co-administered OV to induce a recapitulation of the physiological pathways that lead to optimal (CAR) T cell activation, proliferation and differentiation in vivo in response to virus infection. We have formulated three Specific Aims: 1) To define the molecular mechanisms by which TCR engagement of DS CAR T cells determines their phenotype, improved persistence and function; 2) To generate in vivo expanded populations of DS CAR T cells with TCR specificity against either tumor associated, or viral recall, antigens and to determine their therapeutic activity against established tumors; 3) To optimize in vivo expansion, persistence/longevity and re-activation of DS CAR T cells through novel boost and rest strategies targeting either the TCR, CAR or both. This will lead to implementation of fully systemic protocols for the combination of CAR T cells with OV which do not require any access to tumors.


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 = $327,341 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	4	12/9/2025	NON-COMPETING CONTINUATION	$327,341
														Subtotal = $327,341

Issue Date FY: 2025 ( Subtotal = $363,713 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	3	11/25/2024	NON-COMPETING CONTINUATION	$327,341
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	3	5/30/2025	NON-COMPETING CONTINUATION	$36,372
														Subtotal = $363,713

Issue Date FY: 2024 ( Subtotal = $345,528 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	2	11/28/2023	NON-COMPETING CONTINUATION	$327,341
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	2	4/18/2024	NON-COMPETING CONTINUATION	$18,187
														Subtotal = $345,528

Issue Date FY: 2023 ( Subtotal = $363,713 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	11/30/2022	NEW	$363,713
														Subtotal = $363,713

Grand Total All Awards = $1,400,295

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Re-purposing Oncolytic Virotherapy to Re-invigorate CAR T Cell Therapy for Solid Tumors.

Award Number: R01CA269384

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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