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Democratizing CAR T cell therapy by in situ programming of virus-specific T cells

Award Number: R00CA276890
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Democratizing CAR T cell therapy by in situ programming of virus-specific T cells - Engineered T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against hematological malignancies. However, broad implementation of CAR T cell therapies is limited by the lengthy (3–5 weeks) and costly ($350K–450K per treatment) ex vivo manufacturing pipeline. This proposal seeks to develop antigen-presenting nanoparticles (APNs) for in situ programming of virus-specific T cells for rapid and cost-efficient CAR T cell manufacturing. Virus-specific T cells present a promising opportunity to enhance CAR T cell therapy, as they have improved persistence and proliferation potential, and allow for viral vaccination to augment CAR therapy through their endogenous receptors. This proposal will focus on influenza A virus (IAV)- specific T cells to exploit the existing seasonal influenza vaccination to boost CAR activities. To deliver CAR to IAV-specific T cells, APNs will comprise lipid nanoparticles (LNPs) that encapsulate CAR-encoded mRNA and are decorated with HLA-A peptide-major histocompatibility complex (pMHC) displaying influenza peptide epitopes. This proposal will use APNs to deliver human B-cell maturation antigen (BCMA) CAR in the context of multiple myeloma with future goals to expand to other CAR specificities and indications, including CD19 positive cancers. The goal in Aim 1 is to develop APNs for transfection of human influenza-specific T cells with αBCMA CAR in vivo, and characterize the CAR transfection specificity in the target IAV-specific T cells versus other major cell populations. Aim 2 will be focused on validating the anti-cancer efficacy of αBCMA CAR T cells after in situ transfection using a mouse model recapitulating human multiple myeloma. The vaccination strategy to expand IAV-specific T cells and to boost their effector functions will be tested using inactivated influenza virions to vaccinate the CAR-expressing, IAV-specific T cells and compare the resulting anti-cancer potency with the unvaccinated cohort. In Aim 3, CRISPR/Cas9 will be implemented with APNs for in vivo gene editing of T cells with CAR for durable CAR expression and enhanced anti-cancer potency by delaying T-cell differentiation and exhaustion. The success of this proposal will challenge existing paradigms of T cell engineering, reduce the cost of CAR T cell therapy, and enhance anti-cancer activity through influenza vaccination to ultimately democratize CAR T cells for cancer therapy. Through this work, the candidate will close the knowledge gaps by the mentorship of an exceptional advisory committee: (1) Gabe Kwong, Ph.D. (CAR T cell engineering), (2) Phil Santangelo, Ph.D. (mRNA therapeutics and CRISPR/Cas), (3) Rafi Ahmed, Ph.D. (anti-viral T cell immunity and memory/exhaustion T cell biology), and (4) Madhav Dhodapkar, M.D. (hematology/oncology and myeloma cancer models). This strong mentoring team and the abundant resources provided by Georgia Tech and Emory University constitute a fertile mentoring environment for attaining the candidate's career goal of leading an independent research program focused on developing new technologies to improve patient access and treatment outcome of T-cell immunotherapy against cancer.


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 = $249,000 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	3	4/27/2026	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $249,000

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Democratizing CAR T cell therapy by in situ programming of virus-specific T cells

Award Number: R00CA276890

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/08/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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