Cytokine therapies for cancer largely have not lived up to their preclinical promise, due to limited efficacy as well as toxicity. Now, an engineered version of the cytokine IL-18 has shown antitumor efficacy and low toxicity in mouse models. A team of researchers led by Aaron Ring, MD, PhD, associate professor of immunobiology at Yale University, developed the novel cytokine to evade a binding protein in the tumor microenvironment that blocks its activity. The work was published in Nature.1

To advance this new molecule as a potential immunotherapy, Dr Ring founded Simcha Therapeutics, which launched in June with $25 million in funding. The company’s investors include WuXi AppTec’s Corporate Venture Fund, Sequoia Capital China, and Connecticut Innovations.

“One thing that makes me personally excited about IL-18 therapy relates to its mechanism of action,” said Dr Ring. “Not only is it going to be a first-in-class molecule, but it’s a very different signal than has been delivered by other agents.”

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Simcha aims to file an investigational new drug (IND) application early next year, with the goal of beginning a phase 1 trial in the first half of 2021. The trial will include patients with a variety of solid tumors that have been refractory to standard therapies, including immunotherapy. “We’re not targeting any 1 particular type of tumor,” explained Dr Ring, “but we are definitely thinking about tumor types that may express the binding protein as good ones to look at in the cohort expansion study.”

The researchers found that tumor-infiltrating lymphocytes (TILs) expressed more IL-18 receptors than other T cells. “Compared to other cytokine pathways that are currently being developed, like IL-2 and IL-15, this one was a lot more selective toward these TIL in comparison to general T cells,” said Dr Ring. Frustratingly, however, previous clinical trials of IL-18 show that while it was well tolerated, it had poor efficacy.2

“This was a shocking paradox,” Dr Ring wrote in a June 24 Twitter thread describing the work. Suspecting that an inhibitory factor might be in play, Dr Ring and his team investigated the IL-18 pathway components in a variety of mouse tumors. Sure enough, they identified an IL-18 binding protein (IL-18BP) that was highly expressed in the tumor microenvironment. This protein, or “decoy receptor,” was tying up all the IL-18 and preventing it from activating the TILs.

“The idea of human physiology having systems where we can regulate and soak up excess proteins is an exciting frontier,” said Jamie Spangler, PhD, assistant professor of biomedical engineering at Johns Hopkins University, Baltimore, Maryland. “This is a very profound discovery in the IL-18 system that this is occurring, and being able to engineer and manipulate the pathway is very exciting.”

To activate an antitumor immune response, IL-18 had to somehow escape the binding protein.