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IDO1 and Immunotolerance in Glioblastoma

Award Number: R01NS097851
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: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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IDO1 and Immunotolerance in Glioblastoma - PROJECT SUMMARY This R01 renewal proposal intends to extend the PI's past productivity that includes 35 publications since the year, 2016, including 3 senior-authored manuscripts in Clinical Cancer Research and 2 additional bodies of work that are under review in Neuro-Oncology and Nature. The scientific premise of the PI's renewal application is an extension of continuous NIH/NINDS F32 (Postdoctoral NRSA), NIH/NINDS K99/R00 (Pathway To Independence) and NIH/NINDS R01 support that have collectively focused on the investigation of indoleamine 2,3 dioxygenase 1 (IDO; IDO1) in glioblastoma (GBM). IDO is expressed in >90% of all patient-resected GBM and potently suppresses the anti-GBM immune response. IDO expression is increased by GBM-infiltrating T cells and therefore represents a key mechanism of resistance to immune-based therapies, since targeted approaches that aim to enhance T cell infiltration into GBM, will in-turn, result in a compensatory increase of IDO expression and suppression of the anti-GBM immune response. Importantly, the high intratumoral IDO expression is associated with significantly decreased GBM patient survival and increased immunosuppressive regulatory T cells (CD4+CD25+FoxP3+). Since IDO is canonically characterized as a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream metabolite, kynurenine (Kyn), the depletion of Trp and/or accumulation of Kyn has been the presumed mechanism of how IDO suppresses the anti-GBM immune response. However, our work has challenged this hypothesis, supported in-part through the creation of IDO-deficient murine GBM cells reconstituted with either (i) empty expression vector, (ii) a vector expressing wild-type IDO, (iii) or a vector expressing enzyme-inactive IDO. When intracranially-engrafted into the syngeneic mouse brain, GBM cell IDO expression increases Tregs and decreases survival independent of tryptophan metabolism. Our collective results indicate that GBM cell IDO represents a complex mechanism of immune resistance that has motivated our development of IDO-proteolysis targeting chimeras (IDO-PROTACs) - compounds that bind to IDO protein and recruit an E3 ubiquitin ligase to facilitate proteasome degradation. IDO-PROTACs enable experiments to address IDO immunosuppressive effects that are enzyme independent. The aims of our proposal are therefore to (i) investigate the mechanism responsible for GBM cell IDO enzyme independent immunosuppression and (ii) design, create and optimize novel IDO-PROTACs that mediate IDO protein degradation in human GBM cells. Determination of how IDO suppresses the immune response combined with the generation of potent IDO-PROTACs will address knowledge gaps about GBM immunobiology while also improving treatment outcomes of GBM patients that are co-treated with immunotherapy and IDO-PROTACs.


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 = $502,054 )
2025	2025	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/20/2025	NON-COMPETING CONTINUATION	$502,054
														Subtotal = $502,054

Issue Date FY: 2024 ( Subtotal = $487,318 )
2024	2024	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/28/2024	NON-COMPETING CONTINUATION	$487,318
														Subtotal = $487,318

Issue Date FY: 2023 ( Subtotal = $515,890 )
2023	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	8/4/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$13,500
2023	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	8	9/13/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$426,414
2023	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	8	8/22/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2023	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	7/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$502,390
2023	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/27/2023	NON-COMPETING CONTINUATION	$0
2023	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	7	9/13/2023	NON-COMPETING CONTINUATION	-$426,414
														Subtotal = $515,890

Issue Date FY: 2022 ( Subtotal = $628,320 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	7/19/2022	NON-COMPETING CONTINUATION	$628,320
2022	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/29/2021	COMPETING CONTINUATION	$0
2022	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $628,320

Issue Date FY: 2021 ( Subtotal = $627,010 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	6/16/2021	COMPETING CONTINUATION	$627,010
														Subtotal = $627,010

Issue Date FY: 2020 ( Subtotal = $406,136 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/18/2020	NON-COMPETING CONTINUATION	$406,136
														Subtotal = $406,136

Issue Date FY: 2019 ( Subtotal = $447,531 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	7/10/2019	NON-COMPETING CONTINUATION	$406,629
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/18/2019	SUPPLEMENT FOR EXPANSION	$40,902
														Subtotal = $447,531

Issue Date FY: 2018 ( Subtotal = $336,225 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/26/2018	NON-COMPETING CONTINUATION	$336,225
														Subtotal = $336,225

Issue Date FY: 2017 ( Subtotal = $336,419 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/20/2017	NON-COMPETING CONTINUATION	$336,419
														Subtotal = $336,419

Issue Date FY: 2016 ( Subtotal = $333,868 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/27/2016	NEW	$333,868
														Subtotal = $333,868

Grand Total All Awards = $4,620,771

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IDO1 and Immunotolerance in Glioblastoma

Award Number: R01NS097851

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: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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