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Multi-antigen-specific CAR T cells to treat acute myeloid leukemia

Award Number: K08CA252157
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Multi-antigen-specific CAR T cells to treat acute myeloid leukemia - PROJECT SUMMARY Chimeric antigen receptor (CAR) T cell therapy is a novel form of cellular immunotherapy in which the antigen specificity of T cells is redirected using synthetic receptors. CD19-CAR T cells have achieved complete responses in up to 90% of patients with acute lymphoblastic leukemia. However, many malignancies do not possess a single, highly expressed tumor-associated antigen (TAA) such as CD19. Furthermore, CD19-negative relapses have been frequently encountered following CD19-CAR T cell therapy, suggesting that multi-antigen- targeting approaches will be needed to reduce relapse. Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the majority of patients will die from their disease. We and others are evaluating CAR T cells to treat AML. However, AML exhibits heterogeneous expression of TAAs and many of these TAAs are expressed on hematopoietic progenitor cells (HPCs), increasing the risk of antigen-negative AML immune escape and bone marrow toxicity following AML-targeting CAR T cell therapy, respectively. Additionally, AML employs many active immune-suppressive strategies that may inhibit CAR T cells. To overcome these challenges, I have recently developed a novel viral co-transduction and sorting system to allow generation and purification of T cells with multiple transgenes such as multiple CARs, immune- stimulating molecules, safety switches, and secreted cytokines. Preliminary data suggest that multi-functional CAR T cells can be engineered to overcome antigen-negative leukemia escape and immune suppression mechanisms. I hypothesize that this novel sorting system can be used to engineer T cells to overcome AML TAA heterogeneity and immune suppressive strategies. Aim 1 will investigate CAR T cells simultaneously targeting a set of AML TAAs and predicted to avoid toxicity to HPCs. CAR T cells engineered to overcome AML- induced immune suppression will also be evaluated. In Aim 2 the goal is to target a set of TAAs expressed by both AML and HPCs as part of a pre-transplant CAR T cell immunotherapy strategy. During the award period, the candidate will conduct research at Memorial Sloan Kettering Cancer Center under the mentorship of Dr. Marcel van den Brink and an Advisory Committee. He will obtain the critical skills he needs to become a tenure-track physician-scientist running his own academic laboratory developing synthetic biology approaches to improve cellular therapies and successfully competing for independent NIH funding. He will cultivate a detailed and comprehensive skill set for syngeneic, xenograft, and humanized mouse models of cellular immunotherapy, build upon an existing knowledge base of molecular construct design and cellular gene modification by mastering multiplexed CRISPR/Cas9 gene disruptions and site-specific gene integration, and develop proficiency in genomic analysis to better define T cell activation and exhaustion states and to identify novel targets for gene therapy.


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: 2027 ( Subtotal = $0 )
2027	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	000	5	10/21/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	001	5	8/12/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	4	2/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $263,034 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	001	5	8/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$263,034
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Research Manpower	002	5	9/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	4	8/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $263,034

Issue Date FY: 2023 ( Subtotal = $263,034 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	4	8/25/2023	NON-COMPETING CONTINUATION	$263,034
														Subtotal = $263,034

Issue Date FY: 2022 ( Subtotal = $263,034 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	3	8/4/2022	NON-COMPETING CONTINUATION	$263,034
														Subtotal = $263,034

Issue Date FY: 2021 ( Subtotal = $263,034 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	2	8/20/2021	NON-COMPETING CONTINUATION	$263,034
														Subtotal = $263,034

Issue Date FY: 2020 ( Subtotal = $263,034 )
2020	2020	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Research Manpower	000	1	8/3/2020	NEW	$263,034
														Subtotal = $263,034

Grand Total All Awards = $1,315,170

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Multi-antigen-specific CAR T cells to treat acute myeloid leukemia

Award Number: K08CA252157

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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