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First in Human Phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy

Award Number: R44CA250824
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms that guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example to establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Our preclinical study demonstrate that this outcome is predicated by inactivating the CTLA-4 checkpoint that plays important role in immune tolerance protecting body against autoimmune diseases. Importantly, our studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The irAE is attributable to inactivation of CTLA-4 checkpoint, while the CITE is effective through selective depletion of regulatory T cells (Treg) in tumor microenvironment. We hypothesize that a safer and more effective CTLA-4-targeting immunotherapy should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in tumor microenvironment. In preparation to test this ground-breaking hypothesis clinically, we have generated a new generation of anti- CTLA-4 antibodies that preserving CTLA-4 immune checkpoint by avoiding lysosomal degradation of CTLA-4. The new antibody, ONC-392, has dramatically lower irAEs in humanized mouse model and significantly higher potent activity in depleting tumor-infiltrating regulatory T cells, resulting in more effective CITE. We have conducted IND-enabling studies, including GMP-grade manufacturing and GLP toxicity in non-human primate. We have also sought FDA feedback on our clinical plan through a pre-IND meeting. These progresses allowed us to propose a Fast Track Phase 1/2 SBIR application to determine safety and efficacy of ONC-392 in human cancer patients. With the support of the SBIR grant, we will carry out an open label Phase I/II clinical study to test the safety, pharmacokinetics (PK), and efficacy of ONC-392 as a single agent and in combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients. Our proposed study will not only confirm safety of ONC-392, but also provide clinical proof-of-concept data for our new paradigm of CTLA-4 targeting cancer immunotherapy.


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: 2024 ( Subtotal = $0 )
2024	2022	ONCOC4 INC	9640 MEDICAL CENTER DR	ROCKVILLE	MD	20850	MONTGOMERY	USA	Cancer Treatment Research	000	3	12/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $1,000,000 )
2022	2022	ONCOC4, INC.	9640 MEDICAL CENTER DR	ROCKVILLE	MD	20850	MONTGOMERY	USA	Cancer Treatment Research	000	3	4/4/2022	NON-COMPETING CONTINUATION	$1,000,000
														Subtotal = $1,000,000

Issue Date FY: 2021 ( Subtotal = $938,118 )
2021	2021	ONCOC4, INC.	9640 MEDICAL CENTER DR	ROCKVILLE	MD	20850	MONTGOMERY	USA	Cancer Treatment Research	002	2	8/27/2021	EXTENSION WITH OR WITHOUT FUNDS	$0
2021	2021	ONCOC4, INC.	9640 MEDICAL CENTER DR	ROCKVILLE	MD	20850	MONTGOMERY	USA	Cancer Treatment Research	001	2	4/1/2021	EXTENSION WITH OR WITHOUT FUNDS	$1,000,000
2021	2020	ONCOIMMUNE INC	9430 KEY WEST AVE STE 113	ROCKVILLE	MD	20850	MONTGOMERY	USA	Cancer Treatment Research	000	1	3/19/2021	NEW	-$61,882
														Subtotal = $938,118

Issue Date FY: 2020 ( Subtotal = $400,000 )
2020	2020	ONCOIMMUNE INC	9430 KEY WEST AVE STE 113	ROCKVILLE	MD	20850	MONTGOMERY	USA	Cancer Treatment Research	000	1	4/3/2020	NEW	$400,000
														Subtotal = $400,000

Grand Total All Awards = $2,338,118

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First in Human Phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy

Award Number: R44CA250824

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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