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Optimized Targeting of FLT3 and Menin in KMT2A-R ALL toOvercome Immunotherapeutic Resistance

Award Number: R01CA303979
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/02/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Optimized Targeting of FLT3 and Menin in KMT2A-R ALL toOvercome Immunotherapeutic Resistance - PROJECT SUMMARY The primary hypothesis of this proposal is that targeting highly-expressed leukemia surface antigens with novelantigen chimeric antigen receptor (CAR) T cells and co-modulating epigenetic pathways in KMT2A-rearranged B-lymphoblastic leukemia (ALL) will reduce the emergence of treatment resistance and leukemia relapse following by cellular immunotherapy-induced remissions. These studies have broad relevance for pediatric leukemias given dependencies of numerous acute myeloid leukemia (AML) and ALL subtypes upon epigenetic programing and the demonstrated clinical efficacy of cellular immunotherapies in children with relapsed/refractory B-ALL. In this proposal, we aim (1) to optimize best-in-class FLT3-targeted CAR T cell immunotherapies against KMT2A-rearranged B-ALL and (2) to elucidate the extent to which menin inhibition combined with FLT3CART or CD19CART augments anti-leukemia activity and prevents KMT2A-R ALL relapse, including ALL-to-AML lineage switch. Because primary human leukemia cells are difficult to maintain in longterm cell culture and procurement of necessary leukemia cell numbers from small children for research studies is generally quite difficult, use of animal models for experimental studies are essential for the success of this project. Immunocompromised patient-derived xenograft mouse models of human leukemias have been wellshown to recapitulate the biology of primary human leukemia cells and to be a robust preclinical platform for assessment of the in vivo efficacy and the biochemical effects of therapeutic agents, including CAR T cells and small molecule inhibitors with which our research team has extensive experience. Where possible, alternative approaches such as in vitro studies will be used but will not be sufficient to fully address the goals. The overall goal of these preclinical studies is to identify successful combinatorial immunotherapeutic approaches to mitigate now-known resistance mechanisms of kinase signaling and antigen escape that are imminently translatable to the clinic for early-phase testing in children with high-risk acute 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 = $706,866 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Treatment Research	000	1	7/2/2026	NEW	$706,866
														Subtotal = $706,866

Grand Total All Awards = $706,866

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Optimized Targeting of FLT3 and Menin in KMT2A-R ALL toOvercome Immunotherapeutic Resistance

Award Number: R01CA303979

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/02/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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