Cbl-b inhibition with ISM3830 restores innate and adaptive immunity and demonstrates antitumor activity against solid tumors in vitro and in vivo

Therapeutic inhibition of immune checkpoints, such as CTLA-4 and PD-1/PD-L1, has dramatically improved outcomes for cancer patients, yet there remains a critical need for the majority of patients who relapse or insufficiently respond to current checkpoint inhibitor treatments. Cbl-b is an intracellular immune checkpoint downstream of both CD28 and CTLA-4 signaling that negatively regulates activation of T cells, NK cells, dendritic cells, and mast cells, representing a promising, distinct target for cancer immunotherapy. Here, we describe a novel Cbl-b inhibitor, ISM3830, which demonstrated strong Cbl-b inhibition in vitr o and in vivo , leading to enhanced activation of primary human T cells and NK cells. Comprehensive metabolic and pharmacokinetic profiling showed that ISM3830 has low drug-drug interaction potential, minimal off-target risk, and low in vitro clearance across multiple species. ISM3830 treatment led to increased IL-2 and IFN-gamma release in primary human T and NK cells upon anti-CD3 stimulation, with minimal cytotoxicity up to 10 µM. ISM3830 treatment also restored T cell function in the immunosuppressive tumor microenvironment in the presence of PGE2 or adenosine and significantly recovered the function of exhausted T cells. Oral administration of ISM3830 suppressed tumor growth in CT26 and MC38 syngeneic mouse models, with a significant synergistic effect when combined at a dose of 10 mpk with anti-PD-1, achieving a 96% tumor growth inhibition (TGI) rate and complete tumor regression (CR) in 6 out of 8 animals. Notably, ISM3830 also conferred protection against CT26 tumor rechallenge in cured mice by increasing effector memory T cells and NK cells, indicating ISM3830 induced long-term tumor immunity. In vivo pharmacokinetic studies also demonstrated low clearance (CL < 30% Qh) and an average oral bioavailability of 71% across preclinical species, including mice, rats, dogs, and monkeys. Toxicology studies in mice and dogs indicated a favorable safety profile compared to other small-molecule Cbl-b inhibitors. Human dose projection suggested lower effective doses with sustained target coverage. These data together demonstrate ISM3830 potently activates the innate and adaptive immune responses, sustains antitumor efficacy in animal models, and synergizes with other immune checkpoint inhibitors while maintaining favorable pharmacokinetic and safety profile suitable for clinical development. This work supports the further development of ISM3830 as an immune checkpoint inhibitor to treat various solid tumors.