NEW HAVEN, Conn.--(BUSINESS WIRE)-- Simcha Therapeutics, a biotechnology company developing first-in-class biologic drugs to modulate powerful cytokine pathways, this week shared data at the American Association for Cancer Research (AACR) Virtual Annual Meeting highlighting the potent effects on natural killer cells and stem-like CD8+ cells of its lead asset, a customized variant of IL-18 purpose-built to reverse the immunosuppressive tumor microenvironment.

An oral presentation given by Yale researcher Ting Zhou, Ph.D., detailed findings that the IL-18 variant, which was engineered to avoid the “decoy” receptors that abound in the tumor microenvironment, promotes a strong response by natural killer cells against “cold” tumors – those that are no longer expressing significant MHC Class 1 antigens. NK cells quickly become exhausted and lose efficacy when confronted with tumor cells deficient in MHC Class 1. Those tumors are thus refractory to traditional checkpoint inhibition immunotherapy. The decoy-resistant IL-18 (DR-18) engineered in the lab of Simcha’s founder, Aaron Ring, M.D., Ph.D., showed an ability to rescue those exhausted NK cells and thereby stimulate strong anti-tumor activity in multiple animal models.

Single cell RNA sequencing and flow cytometry revealed that DR-18 promoted functional maturation of highly proliferative NK cells. These newly matured cells retained polyfunctional capacity to produce effector molecules that play a critical role in orchestrating both innate and adaptive immune responses, including IFN-γ, Gzmb, and TRAIL. Ablation of NK cells or neutralization of IFN-γ reversed these effects.

“These results highlight the potential of our tailored cytokine to overcome the immunosuppressive tumor microenvironment and elicit a strong therapeutic response by NK cells, even in cold tumors,” said Dr. Ring. “The single-agent activity of this decoy-resistant IL-18 is compelling, and we are optimistic that it could bring new hope to patients who no longer respond to checkpoint inhibitors. We look forward to bringing this investigational therapy to the clinic in the first half of 2021.”

Dr. Zhou also presented a poster at AACR demonstrating that DR-18 acts on a crucial population of “stem-like” T cells within tumors, increasing their numbers over tenfold and skewing their development toward a highly active effector phenotype, as opposed to an exhausted or dysfunctional state. These results highlight DR-18’s ability to remodel the intratumoral ecosystem to encourage the proliferation of potent anti-tumor effector cells.

“These results make clear that the IL-18 pathway is a powerful target for immunotherapeutic intervention — as long as that intervention avoids the decoy receptors in the tumor microenvironment,” Dr. Ring said. “We’re delighted to be able to share these data with the scientific community at AACR.”

The human variant of the DR-18 is designated ST-067 in Simcha’s pipeline. Simcha is moving through IND-enabling studies and expects to initiate a Phase 1 trial in people with cancer refractory to checkpoint inhibitors in the first half of 2021.

About Simcha Therapeutics

Simcha Therapeutics uses directed evolution to engineer novel cytokines designed to unlock the precision and power of the immune system. Simcha’s lead program, ST-067, is a designer IL-18 cytokine that has shown potent antitumor effects in animal models, both as a monotherapy and when combined with anti-PD-1 checkpoint inhibitors, as described in Nature in June 2020. A Phase 1 trial is expected to be launched in the first half of 2021. Simcha was founded by Aaron Ring, M.D., Ph.D., Assistant Professor of Immunobiology at the Yale School of Medicine. The company has received $25 million in funding to date and is based in New Haven, Conn. For more information, visit www.simchatx.com.

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