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Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants

Award Number: R01CA256006
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants - SUMMARY / ABSTRACT With current treatment options, the five-year survival rate of patients with glioblastoma (GBM) is only 5%. Oncolytic viruses are promising treatments against solid tumors, including malignant gliomas. In a phase I clinical trial evaluating Delta-24-RGD, an oncolytic adenovirus characterized in our laboratory, 20% of recurrent GBM patients receiving the virus achieved a durable response, surviving more than 3 years from the time of treatment, suggesting the existence of a subgroup of patients who would respond to adenoviral treatments. The clinical trial also showed that the efficacy of Delta-24-RGD was due to not only direct tumor cell oncolysis, but also indirect activation of anti-tumor immune responses, a paradigm-shifting finding that radically repositions virotherapy as a type of immunotherapy. Therefore, understanding the interplay between the oncolytic effects of adenoviruses and the viral-mediated anti-glioma immune activation is critical in determining how to increase the efficacy of these promising agents. Our group generated and preclinically characterized an immune agonist-armed version of Delta-24-RGD, named Delta-24-RGDOX, which expresses the T-cell activator OX40L, which will be soon translated to the clinical setting. In this project, we aim to amplify the effect of Delta-24-RGDOX with the administration of inhibitors of the factors that maintain the immunosuppression characteristic of gliomas. Because indoleamine-2,3-dioxgenase (IDO) expression increases significantly after virus infection, we are particularly interested in developing strategies to downmodulate IDO during virotherapy. The catabolism of tryptophan by IDO has important metabolic effects in glioma cells. In addition, the metabolites of tryptophan, including kynurenine (Kyn), activate the aryl hydrocarbon receptor (AhR) that induces Treg differentiation and CD8+ T-cell dysfunction. The central hypothesis of this study is that therapy consisting of Delta-24-RGDOX in combination with IDO and AhR inhibitors will stimulate a cytotoxic immune effect and inhibit the suppressive immune response against the tumor cells, thereby providing a potential effective novel treatment for malignant gliomas. To test this hypothesis, we propose three aims: Specific Aim 1: Examine the activation of the IDO-Kyn-AhR pathway during the infection of gliomas with Delta-24-RGDOX oncolytic adenovirus; Specific Aim 2: Identify the metabolic and immune modifications in the tumor microenvironment produced by the inhibition of the IDO-Kyn-AhR pathway in gliomas treated with Delta-24- RGDOX; and Specific Aim 3: Test the combination of Delta-24-RGDOX and IDO/AhR inhibitors in pre- clinically relevant models of gliomas. This project is the next step in achieving our long-term goal of legitimizing viro-immunotherapy as standard treatment for malignant gliomas.


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 = $370,575 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	002	5	5/22/2025	NON-COMPETING CONTINUATION	$37,057
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	5	2/18/2025	NON-COMPETING CONTINUATION	$333,518
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	5	5/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,575

Issue Date FY: 2024 ( Subtotal = $421,371 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$18,529
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	002	4	6/5/2024	SUPPLEMENT FOR EXPANSION	$69,324
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	4	1/30/2024	NON-COMPETING CONTINUATION	$333,518
														Subtotal = $421,371

Issue Date FY: 2023 ( Subtotal = $363,164 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	1/26/2023	NON-COMPETING CONTINUATION	$363,164
														Subtotal = $363,164

Issue Date FY: 2022 ( Subtotal = $363,164 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	001	2	5/24/2022	NON-COMPETING CONTINUATION	$29,647
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	1/27/2022	NON-COMPETING CONTINUATION	$333,517
														Subtotal = $363,164

Issue Date FY: 2021 ( Subtotal = $370,575 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	1/18/2021	NEW	$370,575
														Subtotal = $370,575

Grand Total All Awards = $1,888,849

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Glioma therapy with oncolytic adenoviruses and immunometabolic adjuvants

Award Number: R01CA256006

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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