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Optimizing Novel Immunotherapy Combinations Targeting the Tumor Microenvironment in Canine Spontaneous Osteosarcoma

Award Number: U01CA224182
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Optimizing Novel Immunotherapy Combinations Targeting the Tumor Microenvironment in Canine Spontaneous Osteosarcoma - Project Abstract Spontaneous canine osteosarcoma (OS) is a well-defined large animal model of human OS, exhibiting similar clinical presentation and molecular aberrations. Indeed, canine OS has historically been used to help develop novel limb spare techniques, evaluate a variety of non-specific immunotherapeutics such as L-MTP-PE, and assess the efficacy of targeted therapeutics to prevent the outgrowth of metastatic disease. Despite best efforts, progress in the prevention and treatment of metastatic disease has essentially stalled for the past 3 decades; 30% of people and 90% of dogs still die of tumor spread, primarily to the lungs. Numerous clinical trials have been undertaken in people with macroscopic metastases and in dogs with both microscopic and macroscopic disease, yet all have failed to demonstrate improved outcomes. This is particularly evident with respect to immune checkpoint inhibitors that do not induce the dramatic disease regressions typically observed in other cancers such as melanoma and lung cancer. One particularly daunting challenge for immunotherapy-based therapeutics in OS relates to the permissiveness of the tumor microenvironment (TME) for inducing anti-tumor immune responses. Our data suggests that a relatively low mutational load combined with a dampened overall immune response in OS may contribute to the observed lack of response to current treatment approaches. We propose that targeting the immune suppressive TME in OS is essential to generating potent and durable anti- tumor immunity. To accomplish this, it may be necessary to simultaneously modulate several elements in the TME, including Tregs, MDSCs, M2 macrophages and overexpressed inhibitory checkpoint molecules. In support of this, we have generated a body of data demonstrating immunological activity of multiple therapeutics, including repurposed drugs with good safety records (losartan, oclacitinib), small molecule inhibitors with established PK/PD in dogs (toceranib, RV1001, reparixin, JHU-292) and antibodies specific for checkpoint molecules (anti- PD1). However, the exact combinations that are most effective against metastatic OS have not yet been identified, and this is a major goal of this proposal. As such, we hypothesize that an adaptive pilot trial design can be used to rapidly screen TME-targeting immunotherapy drug combinations in dogs with macroscopic chemotherapy-resistant metastatic OS and that this information can be refined to assess activity of the most active approach against microscopic metastases in a subsequent adjuvant trial. This will be accomplished by testing four TME modifying immunotherapy combinations for anti-tumor and immune modulatory activity in dogs with macroscopic OS metastases, interrogating relevant biomarkers associated with responses to therapy, then using this information to conduct an adjuvant immunotherapy trial with the most active combination in dogs with microscopic metastatic OS. The data generated from this proposal will create a blueprint for future immunotherapy studies in people with OS by eliminating approaches deemed inactive and generating a set of clinical biomarkers to guide treatment.


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 = -$604 )
2024	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	4	2/15/2024	NON-COMPETING CONTINUATION	-$604
														Subtotal = -$604

Issue Date FY: 2022 ( Subtotal = $570,345 )
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	4	8/17/2022	NON-COMPETING CONTINUATION	$552,171
2022	2022	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	4	9/13/2022	NON-COMPETING CONTINUATION	$0
2022	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	4/18/2022	NON-COMPETING CONTINUATION	$0
2022	2017	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	1	9/26/2022	NEW	$18,174
														Subtotal = $570,345

Issue Date FY: 2021 ( Subtotal = $1 )
2021	2021	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	005	3	9/13/2021	NON-COMPETING CONTINUATION	$1
2021	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	2	1/22/2021	EXTENSION WITH OR WITHOUT FUNDS	-$37,149
2021	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	004	2	4/28/2021	EXTENSION WITH OR WITHOUT FUNDS	$0
2021	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	10/30/2020	EXTENSION WITH OR WITHOUT FUNDS	$922,693
2021	2017	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	10/30/2020	NEW	-$922,693
2021	2017	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	1	1/22/2021	NEW	$37,149
														Subtotal = $1

Issue Date FY: 2020 ( Subtotal = $553,260 )
2020	2020	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	9/10/2020	EXTENSION WITH OR WITHOUT FUNDS	$553,260
2020	2017	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	7/17/2020	NEW	$0
														Subtotal = $553,260

Issue Date FY: 2017 ( Subtotal = $1,672,078 )
2017	2017	COLORADO STATE UNIVERSITY	601 S HOWES ST	FORT COLLINS	CO	80521	LARIMER	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/25/2017	NEW	$1,672,078
														Subtotal = $1,672,078

Grand Total All Awards = $2,795,080

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Optimizing Novel Immunotherapy Combinations Targeting the Tumor Microenvironment in Canine Spontaneous Osteosarcoma

Award Number: U01CA224182

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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