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Novel multipronged Immunovirotherapy Approach for GBM Treatment

Award Number: R01CA258239
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Novel multipronged Immunovirotherapy Approach for GBM Treatment - Project Summary Glioblastoma (GBM) prognosis remains dismal with a median survival of 16-18 months despite the use of multimodality treatment. Immunotherapy attempts have been unsuccessful in GBM treatment, including negative phase III trials of immune checkpoint inhibitors and vaccines. Based on strong preclinical data, we hypothesize that we can develop an effective immunotherapy approach against GBM by employing an immunostimulatory measles virus strain (MV-s-NAP) expressing the Helicobacter Pylori neutrophil-activating protein (NAP), a toll-like receptor 2 agonist. We also hypothesize that MV-s-NAP induced changes in the tumor microenvironment, resulting from immunogenic cell death, can increase efficacy and lead in synergy when combined with immune checkpoint inhibitors. We propose to further enhance the efficacy of this approach by blocking the inhibitory effect of IDO upregulation. We also propose to optimize viral replication in glioblastoma by blocking the interferon response pathway, a known mechanism of mammalian cell resistance to oncolytic viruses, with JAK inhibitors. This project has three specific aims: In specific aim 1, we plan to evaluate the efficacy, optimal sequence and mechanism of action of MV-s-NAP virotherapy in conjunction with antibody blockade of the PD-1/PD-L1 axis and IDO inhibitors in immunocompetent GBM models, including GL261, CT2A, as well as genetically engineered models of spontaneous gliomagenesis. In specific aim 2 we will evaluate the impact of modulating expression of interferon stimulated genes on the efficacy of MV-s-NAP virotherapy and immunovirotherapy by inhibiting the interferon response pathway, which has been shown to decrease viral permissiveness and replication. In specific aim 3 we will test the safety of the optimal efficacy approach identified in specific aims 1 and 2 by conducting toxicology and biodistribution studies in measles replication permissive Ifnarko CD46 Ge mice (an FDA approved model of measles virus replication) in order to determine the safe dose of the combination prior to clinical translation. Safety of the recommended human dose will be further confirmed in a second primate (Rhesus macaques) model. Overall, this work will introduce an innovative multipronged immunovirotherapy approach in the treatment of glioblastoma that has the potential to overcome the lack of efficacy observed with other strategies.


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 = $334,372 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$33,437
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	5	3/4/2025	NON-COMPETING CONTINUATION	$300,935
														Subtotal = $334,372

Issue Date FY: 2024 ( Subtotal = $412,267 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$21,698
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	4	2/21/2024	NON-COMPETING CONTINUATION	$390,569
														Subtotal = $412,267

Issue Date FY: 2023 ( Subtotal = $456,968 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	3	2/23/2023	NON-COMPETING CONTINUATION	$456,968
														Subtotal = $456,968

Issue Date FY: 2022 ( Subtotal = $351,804 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	2	1/28/2022	NON-COMPETING CONTINUATION	$323,084
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$28,720
														Subtotal = $351,804

Issue Date FY: 2021 ( Subtotal = $354,017 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	2/24/2021	NEW	$354,017
														Subtotal = $354,017

Grand Total All Awards = $1,909,428

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Novel multipronged Immunovirotherapy Approach for GBM Treatment

Award Number: R01CA258239

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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