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Engineering Precision Medicine to Enhance Graft-Versus-Lymphoma Effect

Award Number: K23CA222659
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/18/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Engineering Precision Medicine to Enhance Graft-Versus-Lymphoma Effect - Project Summary/Abstract Dr. Satiro De Oliveira, M.D. is an Assistant Professor of Pediatrics in the Division of Hematology/Oncology at UCLA with research interests in biology of transplantation and cancer immunotherapy. His long-term goals are to bring cellular therapy approaches to standard clinical practice. His mentor, Dr. Donald Kohn, M.D., is highly qualified and internationally recognized gene therapy exponent and mentor. A Scientific Advisory Committee has been assembled to combine excellent mentorship skills and expertise in cancer immunotherapy and non- Hodgkin lymphoma to provide guidance for the career development and research plan. Non-Hodgkin lymphomas (NHL) are the fifth most prevalent cancer in the US; patients with refractory or recurrent NHL have less than 50% of chance of cure. The main goal of this proposal is to use gene modification of hematopoietic stem cells (HSC) with chimeric antigen receptors (CAR) targeting CD19, a molecule present in the majority of the NHL. CAR are synthetic chimeric proteins composed of the antigen-recognition portion of a monoclonal antibody fused to intracellular signaling domains able to activate immune cells. CAR-modification of HSC brings the prospect of long-term persistence and CAR expression in multiple hematopoietic lineages, amplifying graft-versus-lymphoma activity; CAR+ HSC could be infused in the context of standard autologous hematopoietic stem cell transplantation. A robust in vivo model of humanized NSG mice engrafted with anti-CD19-CAR-modified HSC has been recently published by Dr. De Oliveira. Detailed evaluation of this approach will lead to a first-in-human clinical trial. A key feature of this K23 application is the use of paired samples of HSC and NHL tumors from patients, with correlation to their demographics, expression of membrane proteins on tumor cells, clinical data and therapeutic outcomes. The scientific questions addressed in this proposal are: Aim 1. Will CAR-modified HSC lead to lasting immunological memory and persistent anti-cancer activity? 1.1. Comparative evaluation of CD28 and 4-1BB co-stimulatory molecules in the anti-CD19 CAR constructs used for modification of human HSC. 1.2. Evaluation of anti-CD19 activity in mice engrafted with CAR-modified human HSC at multiple time-points and after serial tumor challenges. 1.3. Evaluation of the generation of memory T cell subsets from CAR-modified human HSC in mice compared to adoptively transferred CAR-modified human T cells. Aim 2. How robust is the protection of CAR-modified HSC against CD19+ NHL primary tumors? 2.1. Evaluation of humanization of NSG mice with gene-modified HSC from B cell NHL patients. 2.2. Characterization of the phenotype of primary NHL tumor cells using mass cytometry (CyTOF). 2.3. Evaluation of anti-lymphoma activity in humanized mice challenged with primary B cell NHL tumors.


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: 2024 ( Subtotal = -$257 )
2024	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	5	12/13/2023	NON-COMPETING CONTINUATION	-$257
														Subtotal = -$257

Issue Date FY: 2022 ( Subtotal = $183,924 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	5	2/21/2022	NON-COMPETING CONTINUATION	$183,924
														Subtotal = $183,924

Issue Date FY: 2021 ( Subtotal = $183,924 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Research Manpower	000	4	2/12/2021	NON-COMPETING CONTINUATION	$183,924
														Subtotal = $183,924

Issue Date FY: 2020 ( Subtotal = $183,924 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Research Manpower	000	3	2/5/2020	NON-COMPETING CONTINUATION	$183,924
														Subtotal = $183,924

Issue Date FY: 2019 ( Subtotal = $183,924 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Research Manpower	000	2	2/18/2019	NON-COMPETING CONTINUATION	$183,924
														Subtotal = $183,924

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Research Manpower	000	1	6/27/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $183,924 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Research Manpower	000	1	9/18/2017	NEW	$183,924
														Subtotal = $183,924

Grand Total All Awards = $919,363

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Engineering Precision Medicine to Enhance Graft-Versus-Lymphoma Effect

Award Number: K23CA222659

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/18/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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