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Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin

Award Number: R01NS106170
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 04/24/2024

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Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin - Despite research efforts over the past two decades, glioblastoma (GBM) is still a devastating, deadly cancer with a median overall survival of less than 15 months. Oncolytic virotherapy is a promising approach for GBM treatment because it not only involves direct lysis of tumor cells and spares normal cells but also boosts immune responses to tumor cells. However, early clearance of oncolytic viruses by innate immune responses, poor virus propagation in tumor cells, and insufficient viral entry and/or spread present barriers that limit the efficacy of oncolytic virotherapy. In this application, we generated oncolytic herpes simplex virus 1 (oHSV) carrying a “don't eat me signal”, i.e., being engineered to express a ligand, E-cadherin, of the inhibitory receptor of natural killer (NK) cells, KLRG1. This next-generation oHSV carrying E-cadherin (named E-oHSV) reduces the deleterious NK-mediated clearance of oHSV. Importantly, unlike the drugs that we and others previously used to suppress oncolytic virus clearance by innate immune responses, the novel E-oHSV that we generated should not have an immunosuppressive effect systemically or even in the tumor (GBM) microenvironment. That is, E-oHSV only reduces activation of NK cells that bind to or attack E-oHSV-infected cells in the tumor microenvironment, while the remaining NK cells will maintain their potency against GBM cells. E-oHSV also showed enhanced viral production likely by increasing cell-to-cell fusion between virus- infected and uninfected cells. GBM cells do not have endogenous E-cadherin expression; however, interestingly, we found that E-cadherin is not only highly expressed on the surface of E-oHSV-infected cells but also loaded on free viral particles, the latter of which facilitates viral entry and/or spread in solid tumors. These improvements on oncolytic viruses led to significantly enhanced survival of mice bearing patient-derived GBM cells and also prolonged animal survival in an orthotopic, immunocompetent GBM model. In this application, we propose to mechanistically characterize this E-oHSV and to strengthen our hypothesis that a next- generation oHSV expressing E-cadherin, E-oHSV, plays multiple roles to overcome the barriers of oncolytic virotherapy and thus has a superior efficacy for GBM treatment. Three aims have been proposed: Aim 1 is to explore the mechanisms by which innate immune responses to E-oHSV are inhibited. Aim 2 is to explore the mechanisms by which E-oHSV enhances cell-to-cell infection, viral binding, and thus viral spread and distinguish them from the NK inhibition mechanism. Aim 3 is to investigate in vivo mechanisms, efficacy, and potential toxicity of E-oHSV for GBM treatment. Collectively, our study will not only address fundamental questions on NK cell and OV biology, but will also develop novel therapeutics for GBM treatment. It may also provide a platform to enhance efficacy of non-HSV oncolytic viruses.


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 = -$105,524 )
2025	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/29/2025	NON-COMPETING CONTINUATION	-$105,524
2025	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = -$105,524

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $374,912 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/9/2022	NON-COMPETING CONTINUATION	$337,421
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/31/2023	NON-COMPETING CONTINUATION	$37,491
														Subtotal = $374,912

Issue Date FY: 2022 ( Subtotal = $374,912 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/29/2021	NON-COMPETING CONTINUATION	$337,421
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/31/2022	NON-COMPETING CONTINUATION	$37,491
														Subtotal = $374,912

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $380,692 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/7/2020	NON-COMPETING CONTINUATION	$38,069
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/26/2019	NON-COMPETING CONTINUATION	$342,623
2020	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	9/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$294,790
2020	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	9/17/2020	NEW	-$294,790
														Subtotal = $380,692

Issue Date FY: 2019 ( Subtotal = $387,382 )
2019	2019	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$387,382
2019	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/24/2019	NEW	$0
														Subtotal = $387,382

Issue Date FY: 2018 ( Subtotal = $348,382 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/26/2018	NEW	$348,755
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	3/1/2018	NEW	-$373
														Subtotal = $348,382

Grand Total All Awards = $1,760,757

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Overcoming Barriers of Virotherapy by Next-Generation oHSV Expressing E-Cadherin

Award Number: R01NS106170

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 04/24/2024

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