Abstract A36: CA-170, an oral small molecule PD-L1 and VISTA immune checkpoint antagonist, promotes T cell immune activation and inhibits tumor growth in pre-clinical models of cancer

Abstract

Abstract The clinical success of antibody-mediated immune checkpoint blockade therapies has transformed the cancer therapy paradigm by demonstrating that durable antitumor immune responses and long-term remissions may be achieved in a subset of patients across a diverse range of cancers. However, the majority of patients fail to respond to antibody therapies targeting single immune checkpoint pathways and antibodies exhibit a long in vivo half-life (>15-20 days with >70% target occupancy for months) which may contribute to the emergence of immune-related adverse events. Additionally, antibody therapies must be administered by intravenous infusion in a hospital or clinic which places an additional burden on patients who may have mobility challenges. Thus, there is a significant opportunity for a novel immune checkpoint therapy that can address the shortcomings associated with the current antibody therapies. CA-170 is a small molecule, orally bioavailable antagonist of the PD-L1, PD-L2 and VISTA/PD-1H immune checkpoint pathways which is currently undergoing Phase I clinical testing. In preclinical safety studies conducted in rodents and non-human primates, orally administered CA-170 shows no signs of toxicity when dosed up to 1000 mg/kg for 28 consecutive days. CA-170 exhibits an oral bioavailability of approximately 40% and <10% in mouse and monkey, respectively, and the plasma half-life ranges from approximately 0.5 hours for mouse to approximately 3.25-4.0 hours for cynomolgus monkey. The ability of CA-170 to disrupt the signaling of PD-1/PD-L1/2 or VISTA/PD-1H has been inferred though in vitro functional studies. CA-170 exhibits potent activity comparable to that of blocking PD-1 or VISTA antibodies when tested in cell culture assays to rescue the proliferation or IFN-γ secretion of lymphocytes stimulated in the presence of inhibitory PD-L1, PD-L2 or VISTA/PD-1H proteins. In mice, orally administered CA-170 inhibits the growth of syngeneic tumors, enhances peripheral T cell activation, and promotes the activation of tumor infiltrating CD8+ T cells in a dose dependent manner. These non-clinical data provide a strong rational for the continued Phase I clinical development of CA-170, the first oral, small molecule immune checkpoint antagonist for the treatment of advanced cancers. Citation Format: Adam S. Lazorchak, Troy Patterson, Yueyun Ding, Pottayil G. Sasikumar, Naremaddepalli S. Sudarshan, Nagaraj M. Gowda, Raghuveer K. Ramachandra, Dodheri S. Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant. CA-170, an oral small molecule PD-L1 and VISTA immune checkpoint antagonist, promotes T cell immune activation and inhibits tumor growth in pre-clinical models of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A36.