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Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells

Award Number: R01CA247550
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 04/24/2024

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Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells - NK cells are the first line of defense against tumor cells. We recently developed CAR NK cells for the treatment of multiple myeloma (MM), which demonstrates improved anti-MM activity. However, challenges still exist for NK cell- based cancer immunotherapy: some tumor cells are resistant to cytotoxicity of NK cells that have a short life span after infusion into patients. Thus, further understanding of NK cells will be critical to better harness this population for immunotherapy. Our data recently published in Nature Immunology show that an important transcription factor, XBP1s, encoded by an unconventionally spliced mRNA of X-box binding protein (XBP1), positively regulates NK cell survival and effector functions. XBP1s regulates NK cell cytotoxicity and GZMB gene expression via direct promoter binding. XBP1s physically interacts with T-BET, a master regulator in NK cells, suggesting that XBP1s can recruit T-BET to the promoters of target genes. This discovery fills a current gap in the field, as T-BET is known to positively regulate the expression of GZMB despite lacking direct T-BET binding sites on the GZMB promoter. Moreover, IL-15, one of the most important cytokines regulating NK cell survival, development, and effector functions, activates AKT signaling to increase stability of XBP1s protein via deubiquitination, leading to XBP1s nuclear accumulation. Consistent with these human data, conditional knockout of Xbp1 in mice shows a decreased number of NK cells and impaired NK cell anti-tumor activity. We believe that we have identified a novel IL-15-AKT- XBP1s signaling pathway that plays key roles in regulating multiple aspects of NK cell biology. Thus, our overall hypothesis is that this IL-15-AKT-XBP1s signaling pathway newly identified by our group positively regulates NK cell survival and effector functions and can be utilized to improve NK cell or CAR NK cell- based cancer immunotherapy. We propose mechanistic studies regarding how XBP1s regulates NK cell survival and effector functions. We also propose combinational therapies of IL-15/IL-15Rα with CS1-CAR NK cells or with B-I09, a novel drug targeting XBP1 splicing to XBP1s that has strong activity in treating various cancers including MM. IL-15/IL-15Rα can selectively stabilize the XBP1s protein and prevent B-I09-mediated downregulation of XBP1s and the associated inhibition of functions in NK cells. We will engineer CS1-CAR NK cells to express IL- 15/IL-15Rα or XBP1s to have enhanced in vivo persistence of these cells for continuous tumor eradication. Three Aims are proposed. Aim 1: Study the mechanism and functional consequences of enhanced XBP1s protein expression levels via IL-15-AKT signaling in NK cells. Aim 2: Study whether and/or how XBP1s regulates NK cell survival, proliferation, and trafficking. Aim 3: Study the role of XBP1s in combination therapies of IL-15/IL-15Rα with a novel drug targeting XPB1s, B-I09, and/or with CS1-CAR NK cells for the treatment of MM. Our project is significant and timely as IL-15 and IL-15/IL-15Rα are top agents for cancer immunotherapy and are being actively tested in the clinic. Our studies will lead to new insights into NK cell biology, improve outcomes for NK cell-based immunotherapy, and facilitate developing innovative cancer immunotherapeutics.


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 = -$171,933 )
2025	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	10/18/2024	NON-COMPETING CONTINUATION	-$171,933
														Subtotal = -$171,933

Issue Date FY: 2024 ( Subtotal = $423,402 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$22,284
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	002	5	9/11/2024	NON-COMPETING CONTINUATION	$0
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	5	11/20/2023	NON-COMPETING CONTINUATION	$401,118
														Subtotal = $423,402

Issue Date FY: 2023 ( Subtotal = $436,772 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	4	3/14/2023	NON-COMPETING CONTINUATION	$35,654
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	4	11/8/2022	NON-COMPETING CONTINUATION	$401,118
														Subtotal = $436,772

Issue Date FY: 2022 ( Subtotal = $436,772 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	3	11/4/2021	NON-COMPETING CONTINUATION	$401,118
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	3	5/5/2022	NON-COMPETING CONTINUATION	$35,654
														Subtotal = $436,772

Issue Date FY: 2021 ( Subtotal = $445,687 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	2	1/21/2021	NON-COMPETING CONTINUATION	$22,285
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	2	11/18/2020	NON-COMPETING CONTINUATION	$423,402
														Subtotal = $445,687

Issue Date FY: 2020 ( Subtotal = $445,687 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	000	1	11/28/2019	NEW	$434,945
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	1	1/24/2020	NEW	$10,742
														Subtotal = $445,687

Grand Total All Awards = $2,016,387

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Characterizing and Targeting the Novel IL-15- AKT-XBP1s Pathway in NK Cells

Award Number: R01CA247550

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 04/24/2024

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