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Harnessing the thymus for long-term tumor control with hematopoietic stem cell-derived naive CAR T cells

Award Number: R37CA250661
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Harnessing the thymus for long-term tumor control with hematopoietic stem cell-derived naive CAR T cells - PROJECT SUMMARY Chimeric receptor antigen (CAR) T cells are transforming cancer treatment by providing tumor-specific, molecularly targeted therapies. However, even though current clinical applications of CAR T cell-based cancer immunotherapies such as Kymriah or Yescarta induce remission in most cases, long-term disease control, which is especially needed in pediatric and young adult cancer patients with high-risk malignancies, remains a major clinical challenge. In fact, malignant relapse continues to be the leading cause of death post CAR T cell therapy. Insufficient CAR T cell persistence in vivo is a major obstacle to reducing the risk of relapse and improving survival. We have developed a novel platform for long-lasting tumor immunosurveillance based on continuous in vivo generation of naïve CAR T cells. This proposal is driven by the hypothesis, based on our published and unpublished data, that after the completion of the initial course of intensive chemotherapy long-lasting T cell immunity to cancer antigens can be established by using hematopoietic stem and progenitor cells (HSPCs) engineered to express a tumor cell-targeting CAR and delivered into the patient’s thymus. Image-guided intrathymic injection is a minimally invasive procedure that harnesses the thymus of cancer patients as an in vivo bioreactor, thus offering an innovative and also relatively simple and low-toxic clinical method for sustainable production of highly potent naïve designer T cells from genetically manipulated HSPCs. Direct thymic engraftment of HSPCs (bypassing the bone marrow) eliminates the need for myelo-ablative conditioning while preserving the desired outcome, i.e., long-term generation of naïve antigen-specific T cells. Thymic engraftment will be facilitated by thymic irradiation combined with either cell delivery to the thymus by intrathymic injection or by enhancing the thymic homing capacity of intravenously administered HSPCs by overexpression of thymus- specific homing molecules. We will focus on CD19 CARs as a model system to establish proof of concept of our approach because CD19 CARs have become the gold standard for evaluating novel CAR technologies. Our experimental approaches include strategies designed to allow successful thymic negative selection of CD19 CAR-transduced HSPCs. Over time the project is expected to expand to include a variety of CAR specificities. CAR T cell development from HSPCs will be analyzed both in vitro and in vivo, including assays assessing thymic hematopoietic stem cell maintenance and T cell differentiation from HSPCs within the thymic epithelial microenvironment. We will demonstrate in vivo efficacy (B cell depletion and anti-tumor activity) of the most promising CAR expression system in syngeneic mouse models. Translational studies in humanized mice, including a patient-derived pediatric acute lymphoblastic leukemia model, will be performed during the final year of the project. In sum, this research will test the novel paradigm of CAR T cell development in vivo, promising to make tumor immunosurveillance by CAR T cells broadly available as post-consolidation therapy of high-risk malignancies in pediatric and young adult patient populations.


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 = $539,448 )
2025	2025	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Cancer Biology Research	000	4	1/7/2025	NON-COMPETING CONTINUATION	$485,503
2025	2025	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Cancer Biology Research	001	4	6/3/2025	NON-COMPETING CONTINUATION	$53,945
														Subtotal = $539,448

Issue Date FY: 2024 ( Subtotal = $526,721 )
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$27,724
2024	2024	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Cancer Biology Research	000	3	1/29/2024	NON-COMPETING CONTINUATION	$498,997
														Subtotal = $526,721

Issue Date FY: 2023 ( Subtotal = $543,694 )
2023	2023	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Cancer Biology Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$543,694
														Subtotal = $543,694

Issue Date FY: 2022 ( Subtotal = $592,644 )
2022	2022	HMH HOSPITALS CORPORATION	343 THORNALL ST	EDISON	NJ	08837	MIDDLESEX	USA	Cancer Biology Research	000	1	2/28/2022	NEW	$592,644
														Subtotal = $592,644

Grand Total All Awards = $2,202,507

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Harnessing the thymus for long-term tumor control with hematopoietic stem cell-derived naive CAR T cells

Award Number: R37CA250661

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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