NIH grant: Optimized Targeting of FLT3 and Menin in KMT2A-R ALL toOvercome Immunotherapeutic Resistance (1R01CA303979-01A1)

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NIH grant 1R01CA303979-01A1: Optimized Targeting of FLT3 and Menin in KMT2A-R ALL toOvercome Immunotherapeutic Resistance
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Terry J. Fry. Award: $706866.
Start: 2026-07-02T00:00:00.
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.

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