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Novel mechanisms of acute myeloid leukemia resistance to cell therapy

Award Number: K08CA304485
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Novel mechanisms of acute myeloid leukemia resistance to cell therapy - Acute myeloid leukemia (AML) is a rapidly progressive cancer that occurs in children and adults and has no effective therapies for refractory disease. Chimeric antigen receptor T cell (CART) therapy has achieved impressive rates of response for some leukemias, but CART for AML has not been successful. We lack understanding of the ways AML evades killing by CART therapy. In a recently conducted trial of CART targeting CD123 (CART-123) on AML blasts in adult and pediatric patients, Dr. Bhagwat previously identified an unexpected mechanism of AML resistance whereby activated CART cells secreted cytokines, namely GM-CSF and IL-3, that support AML survival. These cytokines share a receptor, CD131, and subsequently signal via JAK/STAT pathways in AML blasts. Blocking this cytokine- mediated resistance with broad JAK pathway inhibitors may impair CART cells in humans, and thus safely overcoming this AML survival advantage is a key challenge facing AML CART. Elevated STAT5 activity appears to underlie a subgroup of AML patients who had especially poor responses to CART, and understanding this activity will highlight specific vulnerabilities in this group. Dr. Bhagwat’s data also finds that CD131 expression is restricted to AML cells, nominating this as an appealing target. The proposed research aims to 1. develop a detailed understanding of how altered STAT5 levels dictate poor outcomes for AML CART therapies and 2. identify a combination therapy that selectively blocks AML resistance signaling via CD131 while preserving CART anti-leukemia effect. These aims will provide the mechanistic basis for the lack of clinical effect we have observed with AML-directed CART therapies and will identify clinically actionable approaches to prevent resistance and to develop effective CART therapies for AML. As new types of cancer therapies are developed, cancer evolves new means of resistance. The overall objective of this proposal is to understand and overcome novel mechanisms of AML resistance to emerging therapies. This will be accomplished by analyzing patient outcomes in first-in-human clinical studies, and by modeling these outcomes in primary human AML samples. Thus far, results have led to the resurrection of CART-123 with combination therapy to overcome resistance. Dr. Bhagwat’s long-term goal to build a career pursuing this model of patient-informed translational science. To achieve this, Dr. Bhagwat will be mentored throughout the period of this award by Dr. Saar Gill and Dr. Richard Aplenc, as well as by his outstanding mentorship committee consisting of Drs. Kathrin Bernt, Martin Carroll, and Carl June. The proposed training plan will be conducted at the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn), institutions known for being worldwide leaders in cellular immunotherapies. Completion of the proposed research project and the complementary training plan, in this outstanding research and mentorship environment, will provide the candidate a robust foundation to achieve his goal.


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 = $263,656 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	8/17/2026	NEW	$263,656
														Subtotal = $263,656

Grand Total All Awards = $263,656

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Novel mechanisms of acute myeloid leukemia resistance to cell therapy

Award Number: K08CA304485

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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