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Leveraging small molecule inhibitors to improve CD19 CAR T cell immunotherapy for KMT2A-rearranged ALL

Award Number: K08CA286765
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/17/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Leveraging small molecule inhibitors to improve CD19 CAR T cell immunotherapy for KMT2A-rearranged ALL - PROJECT SUMMARY/ABSTRACT This K08 mentored career development award proposal details a research and training plan that is designed to facilitate the career development and transition of Lisa Niswander, MD PhD to an independent physician-scientist investigator. Dr. Niswander is a pediatric oncologist and an Instructor of Pediatrics at the Children’s Hospital of Philadelphia (CHOP) and University of Pennsylvania (Penn). Her long-term goal is to lead an NIH-funded research program focused on the preclinical development and early bench-to-bedside translation of targeted therapies and immunotherapies to improve outcomes for children with leukemia. During the 5-year award period, critical technical and scientific training will be acquired in T cell and chimeric antigen receptor (CAR) T cell immunobiology, single cell transcriptomics, early-phase clinical trial design, leadership, and scientific communication. Under the primary mentorship of Dr. Sarah Tasian, a leader in the development of molecularly- targeted and CAR T cell therapies for high-risk pediatric leukemias, and co-mentorship of Dr. Martin Carroll, an expert in acute leukemia signaling, in tandem with a complementary advisory committee of senior scientists, this scientific research program and training plan will be bolstered by the resource-rich environment at CHOP/Penn. Despite high cure rates in most children with B-cell acute lymphoblastic leukemia (B-ALL), infants with B-ALL have dismal outcomes. Most cases of infant B-ALL are characterized by KMT2A rearrangements (KMT2A-R) with resulting fusion proteins that complex with critical adaptor protein menin to drive leukemogenesis and/or by frequent activating RAS pathway mutations. Promising preclinical and early clinical efforts have focused on small molecule disruption of KMT2A-menin binding (menin-i) and on MEK inhibitor (MEK-i) blockade of RAS signaling. CD19-directed CAR T cell immunotherapy (CD19CART) has achieved high response rates in children with B- ALL, including infants with KMT2A-R ALL. However, at least 50% of these patients will ultimately relapse. The central hypothesis of this proposal is that combining CD19CART with pharmacologic disruption of specific KMT2A-R ALL biologic vulnerabilities, including menin-binding or aberrant RAS signaling, will improve treatment efficacy and long-term remission in KMT2A-R ALL. To test this hypothesis, the combinatorial strategy of menin- i (Aim 1) and MEK-i (Aim 2) with CD19CART against KMT2A-R ALL will be investigated. The effects of these dual approaches will be elucidated for both anti-leukemia therapeutic activity and for CD19CART functionality and persistence. Successful completion of this career development award will identify promising co-therapeutic strategies with CD19CART poised for rapid clinical translation for children with KMT2A-R ALL. These research and training efforts will also propel Dr. Niswander’s transition to independence by establishing a robust scientific pipeline for future investigation of targeted inhibitors with immunotherapies in pediatric leukemias.


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 = $196,110 )
2026	2026	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	000	4	6/23/2026	NON-COMPETING CONTINUATION	$196,110
														Subtotal = $196,110

Issue Date FY: 2025 ( Subtotal = $196,110 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	005	3	6/24/2025	NON-COMPETING CONTINUATION	$196,110
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	004	1	4/18/2025	NEW	$0
2025	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	003	2	12/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$6,856
2025	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	001	2	12/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$179,046
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	12/20/2024	NEW	-$179,046
2025	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	002	1	12/23/2024	NEW	$6,856
														Subtotal = $196,110

Issue Date FY: 2024 ( Subtotal = $196,110 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	7/17/2024	NEW	$196,110
														Subtotal = $196,110

Grand Total All Awards = $588,330

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Leveraging small molecule inhibitors to improve CD19 CAR T cell immunotherapy for KMT2A-rearranged ALL

Award Number: K08CA286765

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/17/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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