Unlocking the Potential of CA-170: Enhancing T Cell Responses and Suppressing Tumor Growth in Cancer Preclinical Models

Antibody-based immune checkpoint therapies have revolutionized cancer treatment, offering sustained immune responses and long-term remissions for some patients with various cancers. However, many patients do not benefit from these therapies, which target single pathways and have a prolonged in vivo half-life that can lead to adverse events. Moreover, the need for intravenous administration at medical facilities can be challenging for patients with mobility issues. There is a clear need for an innovative immune checkpoint therapy that overcomes these limitations. CA-170 is a novel, orally administered small molecule that antagonizes PD-L1, PD-L2, and VISTA/PD-1H pathways and is currently in Phase I clinical trials. Preclinical studies in rodents and primates have shown no toxicity at dosages up to 1000 mg/kg for 28 days. CA-170 has an oral bioavailability of around 40% in mice and less than 10% in monkeys, with plasma half-life varying from 0.5 hours in mice to 3.25-4.0 hours in cynomolgus monkeys. In vitro studies suggest that CA-170 can disrupt PD-1/PD-L1/2 or VISTA/PD-1H signaling and has been shown to be as effective as antibodies in promoting lymphocyte proliferation and IFN-γ secretion in the presence of inhibitory proteins. In mice, CA-170 has been shown to inhibit tumor growth, enhance T cell activation, and activate tumor-infiltrating CD8+ T cells in a dose-dependent manner. These findings support the ongoing clinical development of CA-170 as a first-of-its-kind oral small molecule immune checkpoint antagonist for advanced cancer treatment. The research was presented by Adam S. Lazorchak and colleagues at the AACR Special Conference on Tumor Immunology and Immunotherapy in 2016.