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Inhibiting Free Fatty Acid Transport to Improve CAR-T Cell Therapy of Relapsed B-cell Acute Lymphoblastic Leukemia

Award Number: R37CA295527
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/20/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Inhibiting Free Fatty Acid Transport to Improve CAR-T Cell Therapy of Relapsed B-cell Acute Lymphoblastic Leukemia - Inhibiting Free Fatty Acid Transport to Improve CAR-T Cell Therapy of Relapsed B-cell Acute Lymphoblastic Leukemia Abstract Chemotherapy-resistant B-cell acute lymphoblastic leukemia (B-ALL) remains a leading cause of cancer-related death for children and young adults. While CD19-directed chimeric antigen receptor T cell (CAR-T) therapy offers promise for relapsed/refractory cases, high long-term failure rates necessitate a deeper understanding of resistance mechanisms. Our preliminary studies highlight free fatty acid (FFA) uptake inhibition as a potential metabolic vulnerability in human B-ALL to enhance CAR-T efficacy, particularly in cases harboring TP53 mutations associated with relapse and chemotherapy resistance. Using genome-wide CRISPR/Cas9 screening on TP53-wildtype and TP53-mutated CD19+ B-ALL cell lines exposed to CD19-CAR-T treatment, we identified the targeting of fatty acid transporter FATP2 (encoded by SLC27A2) as a candidate for enhancing CAR-T efficacy. Subsequent pediatric B-ALL patient cohort analyses correlated high SLC27A2 mRNA expression with worse overall survival. FATP2-expressing B-ALL lines exhibited increased long-chain FFA uptake, with in vitro studies validating a leukemia-intrinsic role for FATP2 in promoting CD19 CAR-T resistance, with reversible effects upon depleting exogenous FFA. Stable isotope FFA uptake tracing revealed a role for FATP2 in promoting succinate accumulation in TP53-mutated B-ALL cells, which may impact leukemic gene expression through α-ketoglutarate inhibition. This proposal seeks to evaluate exogenous FFA uptake inhibition via genetic and pharmacological FATP2 inhibition to overcome CAR-T resistance in human B-ALL cell lines in vivo and primary B-ALL patient biospecimens ex vivo. Through metabolomic analyses and stable isotope-labeled linoleic acid tracing, we will then elucidate the precise metabolic pathways impacted by FATP2-dependent FFA utilization in primary human B-ALL, including investigating the mechanistic impact of succinate accumulation on TP53-mutated B-ALL gene expression and its role in CAR-T responsiveness. This interdisciplinary research seeks to enhance CD19 CAR-T therapy for relapsed/refractory B-ALL by targeting FFA uptake and uncovering gene-regulatory changes. The study aims to determine whether succinate or related metabolic intermediaries mediate B-ALL cell survival during CAR-T therapy. The comprehensive approach leverages the expertise of a diverse research team, ensuring a nuanced understanding of B-ALL biology and potential avenues for improving CAR-T-treated B-ALL patient outcomes.


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 = $417,865 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Treatment Research	000	2	12/19/2025	NON-COMPETING CONTINUATION	$417,865
														Subtotal = $417,865

Issue Date FY: 2025 ( Subtotal = $481,818 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Cancer Treatment Research	000	1	1/17/2025	NEW	$481,818
														Subtotal = $481,818

Grand Total All Awards = $899,683

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Inhibiting Free Fatty Acid Transport to Improve CAR-T Cell Therapy of Relapsed B-cell Acute Lymphoblastic Leukemia

Award Number: R37CA295527

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/20/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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