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TNF-alpha-"armed" TCR vectors to enhance adoptive cell therapy for solid tumors

Award Number: R37CA289813
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/11/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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TNF-alpha-"armed" TCR vectors to enhance adoptive cell therapy for solid tumors - PROJECT SUMMARY/ABSTRACT Cancer immunotherapy with T-cells expressing a transgenic T-cell receptor (TCR) or chimeric antigen receptor (CAR) can generate dramatic clinical responses in a variety of solid tumors. However, a significant number of patients do not respond to therapy. We have previously shown that increased secretion activity of tumor necrosis factor alpha (TNF-alpha) is associated with superior clinical responses to TCR-T cell therapy. Furthermore, we have shown that increased TNF-alpha activity reduces immunosuppressive T helper 2 (Th2) cell activity, which is associated with inferior response to therapy due to their anti-effector functionality. We have generated novel lentiviral vectors which simultaneously encode for TNF-alpha along with a tumor antigen-specific TCR or CAR (which we have termed a TNF-alpha-“armed” TCR/CAR vector). Treatment with TNF-alpha-armed TCR-T cells results in enhanced anti-tumor activity in vitro and in vivo in preliminary humanized mouse xenograft studies. Importantly, the improved antitumor functionality was not associated with increased systemic toxicity, due to the antigen-dependent nature of the increased TNF-alpha secretion. We hypothesize that utilizing TNF-alpha-armed TCR/CAR-T cells will result in superior antitumor efficacy of the transgenic T-cells compared to conventional TCR/CAR-T cells. We will explore our hypothesis in a wide variety of TCRs and CARs and associated tumor types via two related but independent aims. Aim 1 will evaluate the impact of transgenic TNF-alpha co-delivery with a transgenic TCR or CAR on T-cell anti- tumor functionality and toxicology in humanized murine xenografts, as well as T-cell infiltration into the tumor microenvironment and gene expression patterns of the tumor tissue in response to the increased TNF-alpha activity via spatial transcriptomics/proteomics. We hypothesize that TNF-alpha-armed TCR/CARs will result in superior anti-tumor functionality in vivo compared to conventional TCR/CAR-T cells without increased toxicity. Aim 2 will explore the T-cell intrinsic impact of increased TNF-alpha activity on T-cell functional phenotype and the underlying signaling mechanisms in the face of chronic antigen stimulation. Tumor-infiltrating lymphocytes obtained from the same humanized mouse xenografts obtained in Aim 1 will be interrogated with mass cytometry, single-cell cytokinetic polyfunctionality assays, and single-cell phospho-proteomics. Repetitive tumor cell stimulation assays in vitro, as well as TNF-receptor-2 knockouts will serve as confirmatory experiments. We hypothesize that the addition of transgenic TNF-alpha to TCR/CAR-T cell therapeutics will augment TNF- alpha/TNF-receptor 2 signaling, leading to inhibition of Th2 immunosuppressive cytokinetic activity. This project represents an innovative approach to improve transgenic T-cell therapeutics and further elucidate the role of TNF-alpha in T-cell biology. Our findings will set the stage for the translation of TNF-alpha-armed TCR/CAR T-cells into the next generation of adoptive T-cell therapies for solid 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: 2025 ( Subtotal = $647,632 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Biology Research	000	1	3/11/2025	NEW	$647,632
														Subtotal = $647,632

Grand Total All Awards = $647,632

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TNF-alpha-"armed" TCR vectors to enhance adoptive cell therapy for solid tumors

Award Number: R37CA289813

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/11/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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