Abstract A206: Small-molecule Cbl-b inhibitors as novel intracellular checkpoint inhibitors for cancer immunotherapy

Abstract

Abstract Cancer cells evade destruction by co-opting checkpoint signaling in the immune system. Therapeutics aimed at preventing this, such as anti-PD1 and anti-CTLA4 antibodies, promote cytotoxic T lymphocyte (CTL)-mediated antitumor immune responses against advanced solid tumors. Harnessing the antitumor activity of CTLs, and that of their innate counterpart natural killer (NK) cells, is a promising approach. Activation of CTLs and NK cells is tightly regulated. CTLs require costimulatory signals, such as CD28, for robust activation. NK cell activation can be kept in check by a variety of inhibitory receptors, such as those of the TAM tyrosine kinase receptor family. Ultimately, these signaling events are orchestrated by the ubiquitin signaling system. One ubiquitin ligase in particular, Cbl-b (Casitas B-lineage lymphoma proto-oncogene b), is a negative regulator of both CTL and NK cell activation. In T cells, Cbl-b attenuates TCR signaling by negatively regulating several downstream signaling components, enforcing the requirement for costimulation. In NK cells, Cbl-b regulates TAM receptor internalization at the plasma membrane via ubiquitylation, and this process is important in enabling inhibitory signaling via the TAM receptors. Accordingly, mice deficient in active Cbl-b exhibit hyper-responsive immunity and reject a variety of implanted metastatic and nonmetastatic tumors. Outgrowth of spontaneous tumors in these mice is also significantly delayed. This tumor resistance is mediated by activated CD8+ T cells and NK cells. Thus, Cbl-b is a promising target for developing small-molecule cancer immunotherapy agents. Using proprietary HTS technologies, Progenra has discovered novel and selective Cbl-b inhibitors that decrease ubiquitylation of TAM receptor family members (Tyro3). These inhibitors also promote CD3-mediated activation of T cells in a CD28-independent manner, markedly increasing proliferation, IL-2 secretion, and TNFα production in T cells. Additionally, these Cbl-b inhibitors increase NK cell activation (as measured by IFNγ and degranulation) in ex vivo assays. ADME/DMPK as well as in vivo efficacy data will be discussed. These molecules are expected to synergize with other approved immunotherapy agents. Citation Format: Christopher Riling, Ivan Sokirniy, Brigid Cunnion, Emily Todd, Michael Mattern, Jian Wu, Taku Kambayashi, Suresh Kumar. Small-molecule Cbl-b inhibitors as novel intracellular checkpoint inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A206.