Abstract 2400: K01401-020 is a novel anti-VISTA antibody for cancer treatment: Pharmacodynamic impact on non-human primates and human immune system

Abstract

VISTA (V-domain Ig suppressor of T cell activation), also known as PD-1 homolog (PD-1H), is a transmembrane protein which is highly expressed in myeloid cells such as neutrophils, monocytes, macrophages, and dendritic cells, and at low levels on naive CD4, CD8 and regulatory T-cells. VISTA is also expressed in cancer cells in some patient subsets (Villarroel-Espindola, 2017; Boger, 2017; Liao, 2018). VISTA is functionally described as a negative checkpoint regulator of immune response. Hence, VISTA blockade increases proliferation when T cells are stimulated with VISTA expressing myeloid antigen presenting cells (Wang et al, 2011). Immune suppression by VISTA-positive cells has been hypothesized in the primary or acquired resistance to cancer immunotherapy (Kakhavand, 2017); and even a negative impact of VISTA on immune response has been functionally demonstrated in prostate cancer samples from patients having received prior immunotherapy (Gao, 2017). Here we show that VISTA RNA and protein are expressed in lung cancer samples. We also show by using bioinformatics, that VISTA expression is linked to the higher myeloid infiltrated tumors and can also be found in tumor cells. K01401-020 is novel monoclonal, humanized IgG antibody that binds to cynomolgus monkey and human-VISTA (hVISTA) with a high affinity (Kd ~0.1 nM). The antibody binds to VISTA extracellular domain and blocks its associated function. The pharmacology of K01401-020 was studied in a series of in vitro (ex vivo) experiments with human blood cells, and in vivo studies in non-human primates. Peripheral Blood Mononuclear cells (PBMCs) from several couples of human donors were mixed together in a Mixed Lymphocyte Reaction (MLR) setting, which showed that K01401-020 stimulated IFNg release after 5 days of culture. K01401-020 stimulates NK cells to proliferate and induces activating cytokines by NK cells and monocytes, contributing to T cell activation. PDL1 expression is also clearly induced on myeloid cells by K01401-020, suggesting that combination therapy with anti-PD1/L1 may be required to optimize the anti-tumor efficacy. In non-human primates, preliminary results show that both K01401-020 monotherapy, given weekly at 3 dose levels for 4 weeks and anti-VISTA antibody combination with anti-PD1 antibody (pembrolizumab) were well tolerated. Pharmacodynamic exploration using peripheric blood sampling demonstrated full VISTA occupation by the antibody, and notably, dendritic cell activation. K01401-020 antibody drug is thus expected to increase global and specific anti-tumor immune response in situations where VISTA is expressed in cancer patients and may be synergistic with anti-PD1/L1 antibodies. Citation Format: Noureddine Loukili, Isabelle Vandenberghe, Olivier Delfour, Francoise Fraboul, Eric Chetaille, Francisco Cruzalegui, Nathalie Corvaia, Pierre J. Ferre. K01401-020 is a novel anti-VISTA antibody for cancer treatment: Pharmacodynamic impact on non-human primates and human immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2400.