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Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors

Award Number: R01CA214062
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors - Targeting VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation) can eradicate large, established tumors that are resistant to PD-1/CTLA-4 blockade (“checkpoint-resistant” tumors). We propose this is because anti-VISTA can relieve T cell suppression and also reduce the myeloid-derived suppressor cell (MDSC) composition and function within the tumor microenvironment (TME). To our knowledge, there is no other antibody-based therapy that results in this outcome. Furthermore, data in human tumors are showing that high levels of VISTA expression in the TME is correlated with poor survival. The mission of this proposal is to define the mechanisms underlying the anti-VISTA pro-survival impact in established tumors. The emerging recognition that VISTA is functionally bi-directional, acting as both a ligand and a receptor and is expressed on multiple hematopoietic lineages (T cells, myeloid) opens up an expanding breadth of mechanisms that could account for its role in T cell suppression and MDSC function. We present VSIG8, another Ig supergene family member that we identified as the VISTA counter-receptor. Specific Aim #1 tests two hypotheses that explain VISTA-mediated suppression. First, that VISTA, acting as a ligand expressed on APCs/MDSCs, triggers suppression of T cells through VSIG8. Second, VISTA expressed on T cells, acting as a receptor, when engaged by VSIG8 triggers T cell suppression. These are two distinct hypotheses that could account for the VISTA-mediated immune suppression in cancer. Their resolution will bring decisive new information on the mechanisms of anti-VISTA action in tumor immunotherapy. Specific Aim #2 addresses yet another new fundamental role of VISTA as a receptor that controls MDSC function. We report that VISTA targeting results in a striking reduction of Ly6G+ MDSCs and tumor associated macrophages (TAMs) within the TME. Additional studies confirm a central and profound immunoregulatory role of VISTA in controlling MDSC biology (mediator production, chemotaxis, etc). We propose that the the pleiotropic effects of VISTA targeting of MDSCs impacts the immune status of the TME and is central to the elimination of “checkpoint-resistant” tumors. All murine studies support the hypothesis that heightened VISTA expression within the TME will impair the development of tumor immunity. The evaluation of mRNA expression of VISTA in colorectal cancer patients revealed a strong correlation between heightened VISTA expression in the TME and shorter overall survival. This correlation was driven by granulocytic and monocytic cell infiltration. In Specific Aim #3 we propose to greatly improve our resolution of VISTA expression in human and mouse colorectal cancer by combined genetic and imaging technologies to define the spatial distribution of VISTA in the TME and define in detail the intensity and distribution of VISTA on TME leukocyte subsets. We propose that these strategies will provide clear and decisive predictive biomarkers and guide the clinical development of anti-VISTA therapies that entered the clinic in January of 2016.


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	2021	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	5	1/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	5	1/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $570,047 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	5	4/12/2021	NON-COMPETING CONTINUATION	$570,047
														Subtotal = $570,047

Issue Date FY: 2020 ( Subtotal = $570,047 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	4	5/22/2020	NON-COMPETING CONTINUATION	$570,047
														Subtotal = $570,047

Issue Date FY: 2019 ( Subtotal = $552,945 )
2019	2019	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	3	4/17/2019	NON-COMPETING CONTINUATION	$552,945
														Subtotal = $552,945

Issue Date FY: 2018 ( Subtotal = $570,047 )
2018	2018	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	2	4/16/2018	NON-COMPETING CONTINUATION	$570,047
														Subtotal = $570,047

Issue Date FY: 2017 ( Subtotal = $570,047 )
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Cancer Biology Research	000	1	4/21/2017	NEW	$570,047
														Subtotal = $570,047

Grand Total All Awards = $2,833,133

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Targeting VISTA eradicates large, established PD-1/CTLA-4 resistant tumors

Award Number: R01CA214062

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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