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A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1

Award Number: R21AI155117
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/13/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1 - PROJECT SUMMARY/ABSTRACT Engineering T cells and natural killer (NK) cells with anti-HIV chimeric antigen receptors (CAR) has emerged as a promising strategy to eradicate HIV-infected cells. Current anti-HIV CARs are mostly designed based on individual broadly neutralizing antibodies (bNAb) recognizing the HIV envelope glycoprotein gp160. However, they are limited by targeting a single epitope, which cannot counter the enormous diversity and mutability of HIV. The overall objective of our proposed research is to develop a universal CAR-NK cell platform that can target various envelope epitopes of different HIV-1 clones. Instead of targeting HIV-1 gp160 directly, we propose to design a CAR recognizing dinitrophenyl (DNP), a small molecular tag. Our central hypothesis is that anti-DNP CAR-NK cells can be redirected to target HIV-1 gp160 by using DNP-modified bNAbs as adaptor molecules. In preliminary studies, we engineer a human NK cell line NK-92 with a CD28/CD3-based anti-DNP CAR. We show that this CAR-NK cell can recognize and kill gp160-expressing cells, and we also find that the epitope location on gp160 affects the ability of DNP-modified bNAb to redirect anti-DNP CAR-NK cells against gp160+ cells. Here, we propose to further test our hypothesis by pursuing two specific aims: 1) Develop and validate an enhanced universal CAR-NK platform to target HIV-infected cells in vitro; and 2) Determine the anti-HIV efficacy of universal CAR-NK cells in humanized mouse models. In the first aim, we will develop new anti-DNP CARs using NK cell-specific signaling domains, such as NKG2D, 2B4, DAP10, and CD16, and we will identify an optimal CAR-NK construct as well as a panel of DNP-modified bNAbs with the highest potency to activate CAR- NK cells against HIV-infected cells in vitro. In the second aim, we will examine the ability of the universal CAR- NK cells, in combination with a cocktail of bNAb-based adaptor molecules, to suppress HIV replication and reduce viral escape in humanized mice infected with HIV. We will also determine whether the universal CAR-NK cells can be coupled with latency reversal reagents to reduce or eliminate latent HIV reservoirs. The proposed research is innovative, in our opinion, because the modular approach is highly flexible and can be used together with essentially any anti-HIV bNAbs. The proposed research is significant because its successful completion will lead to the development of a universal CAR-NK cell prototype with significantly expanded epitope coverage, making it possible to overcome the diversity of HIV-1. This approach, if proved successful, can also be broadly applied for engineering NK cells, T cells, and hematopoietic stem cells to target HIV and other infectious diseases as well as cancer.


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 = -$20,539 )
2025	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	10/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$227
2025	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	10/22/2024	NON-COMPETING CONTINUATION	-$20,312
														Subtotal = -$20,539

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Allergy and Infectious Diseases Research	001	3	4/12/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$98,670
2023	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	4/11/2023	NON-COMPETING CONTINUATION	-$98,670
2023	2021	WESTERN UNIVERSITY OF HEALTH SCIENCES	309 E 2ND ST	POMONA	CA	91766	LOS ANGELES	USA	Allergy and Infectious Diseases Research	002	3	5/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $240,641 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	2	7/9/2021	NON-COMPETING CONTINUATION	$240,641
														Subtotal = $240,641

Issue Date FY: 2020 ( Subtotal = $219,710 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Allergy and Infectious Diseases Research	000	1	7/13/2020	NEW	$219,710
														Subtotal = $219,710

Grand Total All Awards = $439,812

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A Universal CAR-NK Cell Targeting Various Epitopes of HIV-1

Award Number: R21AI155117

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/13/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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