[K08] Novel mechanisms of acute myeloid leukemia resistance to cell therapy
Ente: National Cancer Institute
Scadenza: 2031-07-31
Importo max: 263.656 EUR
Paese: US
Descrizione
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 pr
Istituzione: CHILDREN'S HOSP OF PHILADELPHIA
PI: ANAND BHAGWAT
Progetto: 1K08CA304485-01A1
Settori: National Cancer Institute
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