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Human natural killer cells: Advancing biology and clinical applications

Award Number: R35CA210087
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2032

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Human natural killer cells: Advancing biology and clinical applications - PROJECT SUMMARY The current R35 competitive renewal is revised from 2023 (Score 15). The Panel and Reviewers raised 5 “minor” (the word used in the Summary Statement) weaknesses that I addressed. I have studied the basic biology of human natural killer (NK) cells and their clinical application for cancer treatment over the past 33 years. Basic discoveries from my lab have brought chimeric antigen receptor (CAR) NK cells into the clinic, yet their development for cancer treatment requires improvement. This proposal is built upon our body of work that has been accomplished during the past seven-plus years of this R35 award. We investigated how NK cells develop, survive, kill, and what cell-extrinsic or cell-intrinsic modifications are engaged to enhance these and other properties to improve their clinical efficacy for cancer treatment. This resulted in over 50 publications, including senior authorships in high-profile journals such as Cell, Nature Biotechnology, Nature Immunology (3), Nature Cancer, Immunity (3), Science Immunology, and Cancer Discovery (2). Importantly, we successfully translated our findings into the clinic to treat cancer patients. We now propose to address the key challenges in the field and to improve CAR NK cell therapy. We will: (1) determine the biomarkers and mechanisms that will define NK cell exhaustion, including in vivo models, to reduce or eliminate this effect; (2) investigate whether NK cells possess memory of tumors and if tumors possess memory of NK cells. We will employ novel approaches to define this at the molecular level; (3) elucidate mechanisms by which CAR NK cells traffic into solid tumors; (4) optimize CAR constructs of NK cells for effective anti-tumor activity: and (5) perform IND-enabling studies on CAR NK cells expressing IL-15 to then translate our discoveries into the clinic. This will be exemplified by the proposed IND-enabling studies to translate our published work on anti-PSCA CAR NK cells expressing soluble IL-15 from the past funding cycle (Teng et al., Gastroenterology, 2022) into the clinic to treat pancreatic cancer (PC) patients via institutional funding sources. PC has a 5-year survival rate of 9% and is the 3rd leading cause of cancer-related death. We believe our proposed studies for the next funding cycle will lead to innovative, cost effective, allogeneic, “off-the-shelf”, and safe CAR NK cell therapies to benefit a broader group of cancer patients.


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 = $886,438 )
2025	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Treatment Research	001	8	7/21/2025	COMPETING CONTINUATION	$886,438
2025	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	7	12/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $886,438

Issue Date FY: 2023 ( Subtotal = $954,486 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	7	7/13/2023	NON-COMPETING CONTINUATION	$954,486
														Subtotal = $954,486

Issue Date FY: 2022 ( Subtotal = $954,486 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	6	6/30/2022	NON-COMPETING CONTINUATION	$954,486
														Subtotal = $954,486

Issue Date FY: 2021 ( Subtotal = $973,964 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	6/25/2021	NON-COMPETING CONTINUATION	$973,964
														Subtotal = $973,964

Issue Date FY: 2020 ( Subtotal = $973,964 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	4	6/3/2020	NON-COMPETING CONTINUATION	$973,964
														Subtotal = $973,964

Issue Date FY: 2019 ( Subtotal = $712,108 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	6/10/2019	NON-COMPETING CONTINUATION	$712,108
2019	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	5/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $712,108

Issue Date FY: 2018 ( Subtotal = $992,214 )
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	2	7/31/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$992,214
2018	2018	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	003	2	9/14/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$744,645
2018	2017	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	002	1	9/14/2018	NEW	-$744,645
2018	2017	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	1	7/30/2018	NEW	$0
														Subtotal = $992,214

Issue Date FY: 2017 ( Subtotal = $930,000 )
2017	2017	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Cancer Biology Research	000	1	5/11/2017	NEW	$930,000
														Subtotal = $930,000

Grand Total All Awards = $7,377,660

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Human natural killer cells: Advancing biology and clinical applications

Award Number: R35CA210087

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/21/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2032

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