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Gene delivery to antigen-specific T cells via targeted retroviral vectors to treat cancer

Award Number: R33CA302616
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Gene delivery to antigen-specific T cells via targeted retroviral vectors to treat cancer - Project Summary T cells play a pivotal role in adaptive immunity. Despite immense progress in developing cancer immunotherapies that primarily manipulate T cells, the therapies only work for subsets of patients and subsets of tumor types. In particular, we currently lack an ability to manipulate or genetically reprogram antigen-specific T cells in vivo, which would allow for the ability to combine some of the best attributes of CAR-T therapies (the ability to endow cells with functionality beyond those found in nature) with tumor infiltrating lymphocyte therapies and immune checkpoint blockade (the ability to manipulate a pool of T cells that recognize a range of tumor antigens to minimize the chance of antigen escape). Our proposal addresses this gap by developing peptide-MHC pseudotyped viruses for in vivo gene delivery to antigen-specific T cells, bypassing ex vivo culture steps and avoiding off-target T cells. We previously published a novel lentivirus pseudotyping strategy that makes viral entry dependent on arbitrary, user-defined protein interactions. We have mutated the typical VSV-G envelope protein used in recombinant lentiviral production to eliminate binding to its canonical entry receptor, LDLR. With these mutations, the modified VSV-G retains its ability to fuse virus and cell plasma membranes if the virus can bind to a target cell, decoupling its binding and fusion activity. Thus, co-expressing VSV-dead with a targeting protein expressed on the virus surface uses that protein as a surrogate entry receptor into a cell. We have shown that this approach works for many protein-protein interactions, including antibody-antigen, cytokinecytokine receptor, and key to this application, pMHC-TCRs, even at their typically low endogenous affinities. This enables us to precisely deliver immunomodulatory cargoes to antigen specific T cells while sparing any bystander T cells. We have successfully shown antigen-specific transduction ex vivo and in vivo. In Aim 1 of this current proposal we will streamline parameters for virus production and expand our platform to encompass a wide range of cancer antigens and broad panel of human MHC class I and MHC class II alleles. In Aim 2, we will optimize in vivo transduction of human T cells to minimize off-target transduction rates and improve the safety profile. These experiments will be conducted in mice to evaluate in vivo delivery strategies. Impact: This innovative platform stands to improve cancer immunotherapy accessibility and outcomes


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 = $432,050 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Detection and Diagnosis Research	000	1	8/17/2026	NEW	$432,050
														Subtotal = $432,050

Grand Total All Awards = $432,050

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Gene delivery to antigen-specific T cells via targeted retroviral vectors to treat cancer

Award Number: R33CA302616

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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