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VISTA: A NOVEL THERAPEUTIC TARGET THAT NEGATIVELY REGULATES IMMUNITY

Award Number: R43AI096682
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2011
PERIOD OF PERFORMANCE END DATE: 07/31/2013

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VISTA: A NOVEL THERAPEUTIC TARGET THAT NEGATIVELY REGULATES IMMUNITY - DESCRIPTION (provided by applicant): We have discovered, characterized and functionally defined a novel, immune inhibitory ligand. This ligand is hematopoietically-expressed, a distant member of the B7 Ig-superfamily, and its extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated as V-domain Immunoglobulin Suppressor of T cell Activation (VISTA). Distinct from PD-L1, expression of VISTA is exclusively within the hematopoietic compartment and is highly regulated on myeloid antigen-presenting cells (APCs). A soluble VISTA-Ig fusion protein, or VISTA expression on APCs profoundly inhibits in vitro T cell proliferation and cytokine production. A specific anti-VISTA monoclonal antibody interfered with VISTA-induced suppression of T cell responses by VISTA+ APCs in vitro. VISTA expression on myeloid suppression cells (MDSC) within the tumor microenvironment was expressed at extremely high levels, suggesting that VISTA on MDSCs likely impedes the development of tumor specific immunity by maintaining the suppressive character of the tumor microenvironment. In a murine model of bladder carcinoma, we show that an (VISTA mab that can reverse VISTA suppression, greatly reduced solid tumor growth and enhanced host survival. Due to the preliminary observation that blocking VISTA systemically enhances cell-mediated immunity, we hypothesize that in solid tumors where MDSCs appear to be immunomodulatory, (VISTA therapy will prove to be particularly effective. Unlike many of the other PD-L family members (B7-H3, H4, H6), the hematopoietic restriction (preferentially myeloid) of VISTA together with its profound suppressive activities, and its high expression on MDSCs, makes it a unique target for immune intervention in cancer. Taken together, our findings illustrate that VISTA is a functionally non-redundant, negative regulator of immunity. The Specific Aims of this proposal are: 1) Determine the Effect of aVISTA on Tumor Regression in Murine Models.; and 2) Produce human ahuman VISTA specific monoclonal antibodies. hVISTA-Ig will be used to select GigaMab(tm) mabs through subcontract with BioAtla. BioAtla has constructed and validated a human full length IgG library (GigaMab(tm) Fully Human library) one of the largest numbers of high diversity fully human antibodies expressed in mammalian cells. Using their proprietary bioinformatic analysis tools and rational design strategies, they are expected to maximize the combinatorial diversity of human immunoglobulin heavy and light chains in a custom library to ensure generation of high affinity antibodies. Therapeutic intervention of the VISTA inhibitory pathway represents a novel approach to modulate T cell- mediated immunity for the treatment of a wide variety of cancers. The first indication we will target is ovarian cancer, which kills 13,850 women per year in the US.


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: 2012 ( Subtotal = $300,000 )
2012	2012	IMMUNEXT INC	16 CAVENDISH COURT	LEBANON	NH	03766	GRAFTON	USA	Allergy and Infectious Diseases Research	000	2	8/16/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,000
														Subtotal = $300,000

Issue Date FY: 2011 ( Subtotal = $300,000 )
2011	2011	IMMURX INC	10 WATER STREET	LEBANON	NH	03766	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	8/2/2011	NEW	$300,000
														Subtotal = $300,000

Grand Total All Awards = $600,000

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VISTA: A NOVEL THERAPEUTIC TARGET THAT NEGATIVELY REGULATES IMMUNITY

Award Number: R43AI096682

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2011

PERIOD OF PERFORMANCE END DATE: 07/31/2013

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