Decoy-resistant IL-18: a new paradigm in cytokine therapy
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 1 clinical trial in patients with diverse solid tumors who have progressed on existing immunotherapeutic agents.
October 25, 2022
Depletion of exhausted alloreactive T cells enables targeting of stem-like memory T cells to generate tumor-specific immunity
Science Immunology 7: 76
Simone A. Minnie, Olivia G. Waltner, Kathleen S. Ensbey, Nicole S. Nemychenkov, Christine R. Schmidt, Shruti S. Bhise, Samuel R. W. Legg, Gabriela Campoy, Luke D. Samson, Rachel D. Kuns, Ting Zhou, John D. Huck, Slavica Vuckovic2 Danniel Zamora, Albert Yeh, Andrew Spencer, Motoko Koyama, Kate A. Markey, Steven W. Lane, Michael Boeckh, Aaron M. Ring, Scott N. Furlan, Geoffrey R. Hill
June 24, 2020
IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy
Nature 583, 609–614
Ting Zhou, William Damsky, Orr-El Weizman, Meaghan K. McGeary, K. Patricia Hartmann, Connor E. Rosen, Suzanne Fischer, Ruaidhri Jackson, Richard A. Flavell, Jun Wang, Miguel F. Sanmamed, Marcus W. Bosenberg & Aaron M. Ring
|ST-067 | Monotherapy|
|ST-067 | PD-1 Antagonist Combination Therapy|
|Undisclosed ST-067 Combination Therapies|
|Undisclosed Cytokine Therapeutics|
|ST-067 | Monotherapy||Phase 1|
|ST-067 | PD-1 Antagonist Combination Therapy||Phase 1|
|Undisclosed ST-067 Combination Therapies||Preclinical|
|Undisclosed Cytokine Therapeutics||Preclinical|