Science

Interleukin-18 (IL-18) is an inflammatory cytokine with powerful immunostimulatory activities on key anti-tumor immune cells: tumor infiltrating lymphocytes (TILs) and natural killer (NK) cells. IL-18’s ability to activate both the innate and adaptive branches of the immune system indicates that it could exert a broad spectrum of activity against both immunogenic, or “hot” tumors, as well as “cold” tumors that are resistant to immunotherapy. However, previous clinical experience with recombinant IL-18 therapy revealed a surprising paradox: despite its well-established immunostimulatory activities, IL-18 therapy was ineffective, even in cancer types that have historically responded to immunotherapeutic agents.

Research led by Simcha’s founder Dr. Aaron Ring revealed the basis for natural IL-18’s weak anti-cancer activity. Tumors produce high levels of an IL-18 jamming signal, a “decoy receptor” called IL-18BP. To overcome this problem, Simcha has engineered the first “decoy-resistant” IL-18 variant, ST-067, that is completely impervious to IL-18BP and can maintain strong immune stimulation in the tumor microenvironment. In preclinical tumor studies, decoy-resistant IL-18 demonstrated robust anti-tumor activity by itself and in combination with immune checkpoint inhibitors such as anti-PD-1.

ST-067 is now under evaluation in a Phase 1a/2 clinical trial in patients with diverse solid tumors who have progressed on existing immunotherapeutic agents, including one cohort combining ST-067 with pembrolizumab (Keytruda®). We are also collaborating with researchers at the Fred Hutchinson Cancer Research Canter and separately at the University of Washington to study ST-067 in hematological cancers.