Abstract 5531: K0401-020 anti-VISTA antibody monotherapy increases specific CD8 T cell response in non-human primates
Authors: Libon Christine , Vandenberghe Isabelle , Marlin Romain , Gros Wesley , Leonec Marco , Gomez-Pacheco Mario , Gallouet Anne-Sophie , Fraboul Françoise , Mahfoudi Abderrahim , Dereuddre-Bosquet Nathalie , Ferré Pierre 
Published: September 2020

Background: VISTA is a B7 family protein described as a negative checkpoint of T cell responses, both in autoimmunity and cancer murine models. K01401-020 is a novel IND enabling anti-VISTA antibody. In vitro, when incubated with human blood cells, K01401-020 stimulates NK cells, monocytes and cytokine production, contributing to T cell activation. In vivo, in non-human primates, K01401-020 notably induced dendritic cell activation (Loukili et al, AACR 2019). However, so far, no in vivo demonstration of anti-VISTA pharmacodynamic effect on T cells has been demonstrated beyond mouse models. Thus, we explored the effect of anti-VISTA antibody on CD8 T cell specific activation in non-human primates, using SIV immunization as a model.

Methods: The detection of T cell response amplification by immune-checkpoint inhibitors is very challenging in primates during standard PK or safety studies in the absence of adequate antigen stimulation. KLH is described as an immunogen in monkeys but induces mainly a humoral (IgG/IgM) and not a CD8 response, and thus cannot reveal the pharmacodynamic activity of immune-checkpoint inhibitors. Here, we explored well-described model of primate immunization that induces specifically a cellular response including CD8 (Martinon et al, Hum Gene Ther. 2009) to reveal the activity of Immune-checkpoints inhibitors.

Groups of three adult cynomolgus macaques were immunized thrice with 1mg of MultiSIVmac239 GTU-DNA, by intradermal route with electroporation. One-day after the last immunization, animals received a single intravenous injection of either vehicle, anti-PD1 antibody (pembrolizumab) or anti-VISTA antibody K01401-020. IFNγ ELISPOT assay was performed on PBMCs in the presence of either Nef RM9 peptide or Gag (peptide pool), while RM9 tetramer assay and cell subsets phenotyping were performed on whole blood.

Results: RM9 and gag-specific CD8 responses were evidenced as soon as after the second immunization in at least 2/3 animals from all groups. The third immunization reactivated CD8-specific responses in all groups. Pembrolizumab and anti-VISTA antibody clearly amplified CD8 specific responses respectively in 2/3 and 3/3 monkeys.

Conclusions: Here we show for the first time that a single anti-VISTA antibody infusion monotherapy in non-human primates potentializes specific CD8 T cell responses against exogenous antigen. The above data suggests that anti-VISTA antibody K01401-020 given as a single agent may effectively boosts CD8 T cell activity against tumor antigens.

Confidential – Pierre Fabre and CEA collaboration

Citation Format: Christine Libon, Isabelle Vandenberghe, Romain Marlin, Wesley Gros, Marco Leonec, Mario Gomez-Pacheco, Anne-Sophie Gallouet, Françoise Fraboul, Abderrahim Mahfoudi, Nathalie Dereuddre-Bosquet, Pierre Ferré. K0401-020 anti-VISTA antibody monotherapy increases specific CD8 T cell response in non-human primates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5531.