Monday, June 30, 2025 6/30/2025

Determinants of Resistance to Engineered T-cell Therapies Targeting CD19 in Lymphoma

Award Number: K08CA267307
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Determinants of Resistance to Engineered T-cell Therapies Targeting CD19 in Lymphoma - Project Summary/Abstract The outcomes for patients with large B-cell lymphoma (LBCL) that are relapsed or refractory to frontline therapy remain quite poor. While anti-CD19 chimeric antigen receptor (CAR19) T-cells have emerged as a promising treatment option for this group of patients, over half of these patients still go on to exhibit disease progression. The mechanisms through which resistance to CAR19 T-cell therapy develops, and factors predictive of poor outcomes, have not yet been well characterized. In this proposal we seek to elucidate these mechanisms with the ultimate goal of informing the design of improved immunotherapies that will result in better outcomes for patients with LBCL. Novel methods to profile tumor-derived cell-free DNA from the blood plasma of patients, also referred to as circulating tumor DNA (ctDNA), have unlocked significant opportunities to monitor treatment response and study tumor biology both prior to and after therapy. We recently applied one such method called Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq), a targeted sequencing approach for ctDNA detection and profiling, to a cohort of patients with LBCL undergoing therapy with the CAR19 platform axicabtagene ciloleucel (axi-cel). We found that ctDNA levels prior to and following CAR19 T-cell infusion were predictive of response, and also identified several genes involved in B-cell lineage commitment and determination of the tumor immune microenvironment that were recurrently altered in patients who developed progressive disease. In this proposal we will build on this prior data by validating our findings in an independent cohort of patients undergoing therapy with an alternate CAR19 platform (Aim 1). We will then assess the downstream effects these alterations have on tumor phenotype and the tumor microenvironment. By integrating gene expression data and cutting-edge immunophenotyping and computational tools, we will resolve the components of the intratumoral immune milieu to gain a better understanding of how different immune cell populations contribute to response and resistance (Aim 2). Finally, we will employ a novel organoid tissue culture system to directly assess how alterations in these genes effect the interaction between CAR19 T-cells and tumor cells in the context of an intact immune microenvironment (Aim 3). Ultimately, we hope that these studies will have implications not only in development of improved CAR19 platforms for lymphoma, but also in the improvement of immunotherapies for other cancer types as well. This proposal will be carried out at the Stanford University School of Medicine, under the mentorship of Ash Alizadeh, MD/PhD. Through completion of this proposal, I will gain the relevant experience in bioinformatics and tumor immunology to successfully launch a career as an independent investigator focused on developing and translating new immunotherapies for patients with lymphoma.


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: 2025 ( Subtotal = $188,301 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	002	4	6/9/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$188,301
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Research Manpower	001	3	6/9/2025	NON-COMPETING CONTINUATION	$0
2025	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	2/18/2025	NEW	$0
														Subtotal = $188,301

Issue Date FY: 2024 ( Subtotal = $188,301 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Research Manpower	002	3	6/3/2024	NON-COMPETING CONTINUATION	$188,301
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	11/17/2023	NEW	-$172,946
2024	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Research Manpower	001	2	11/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$172,946
														Subtotal = $188,301

Issue Date FY: 2023 ( Subtotal = $188,301 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	6/30/2023	NEW	$188,301
														Subtotal = $188,301

Grand Total All Awards = $564,903

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Determinants of Resistance to Engineered T-cell Therapies Targeting CD19 in Lymphoma

Award Number: K08CA267307

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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