Abstract 1729: Integrative immune profiling of syngeneic tumor models provides predictive immune signatures for treatment response with HMBD002, a novel anti-VISTA neutralizing antibody
Authors: Jerome D. Boyd-Kirkup, Dipti Thakkar, Konrad Paszkiewicz, Piers J. Ingram
Journal: Cancer Research (2018)

Abstract Myeloid-derived suppressor cells (MDSCs) are a group of immature myeloid cells with potent immune suppressive activity. Accumulation of pathologically activated MDSCs within the tumor microenvironment has emerged as an important mechanism of primary and acquired resistance to immunotherapy. MDSCs have high surface expression levels of V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA), a co-inhibitory negative checkpoint regulator (NCR). Immune suppression by VISTA+ MDSCs has been implicated in the failure of, and resistance to, anti-PD1/PDL1 therapy and represents a unique axis for NCR targeting in the non-responder population. Elucidating the dynamics of VISTA+ MDSCs within tumors is imperative for predicting response and patient stratification. HMBD-002 is a novel anti-VISTA neutralizing monoclonal antibody, developed using Hummingbird Bioscience's proprietary Rational Antibody Discovery platform, against a specific functional epitope on VISTA predicted to be involved in ligand binding. HMBD002 binds human, cyno and murine VISTA protein with high affinity (kD &amp;lt;5nM) and demonstrated a strong, dose dependent inhibition for the interaction of VISTA with its putative ligand VSIG3. In ex vivo PBMC models of immune activation, HMBD002 treatment showed potent induction of cytokine release. Further, HMBD002 monotherapy in a CT26 syngeneic BALB/C model showed significant delay on tumor progression with no observable toxicity. To investigate predictive immune signatures for HMBD002 antibody efficacy, as a monotherapy and in combination with anti- PD-L1 therapy, we established multiple mouse models of tumor immune subtypes using syngeneic cell lines. Tumor biopsies were analyzed before and during treatment, to determine the evolution of immune response and its effect on tumor burden within responders and non-responders. The combination of HMBD-002 and anti-PD-L1 was more effective than either antibody alone, especially in tumors that showed abundant MDSC infiltration. Immune phenotyping revealed that this was associated with a significant increase in activated CD8+ T effector cells and concomitant increase in IFN-gamma. Profiling syngeneic models for deeper insights into the interplay between the tumor, immune system and therapy, will facilitate the clinical development of immune checkpoint and combination therapies. Hummingbird Bioscience anticipates commencing First-in-Human trials of HMBD002 in 2019. Citation Format: Jerome D. Boyd-Kirkup, Dipti Thakkar, Konrad Paszkiewicz, Piers J. Ingram. Integrative immune profiling of syngeneic tumor models provides predictive immune signatures for treatment response with HMBD002, a novel anti-VISTA neutralizing antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1729.