Yale spinout re-engineers an immunotherapy GSK, others once abandoned
Beginning in 2004, GlaxoSmithKline ran 5 different trials to see if giving patients a molecule called IL-18 could treat their cancers. An early form of immunotherapy, it was supposed to boost the body’s natural ability to fight tumors.
It didn’t. The largest of the studies was terminated early; the tumors progressed after around 7 months no matter how much IL-18 you gave them. The field eventually moved on both from IL-18 and, to a degree, from the class of immune modulators, called cytokines, in general.
Failure is par the course in cancer research. Still, this particular failure bothered Yale immunologist Aaron Ring. Similar molecules, IL-2 and IL-15, had been approved as drugs, and when he searched a couple years ago for pathways that may have been overlooked in drug development, the search turned up IL-18; T cells and natural killer cells around the tumor were covered in receptors for it. In theory, you should’ve been able to send IL-18 and stimulate them.
“It looked like this open port we could tap into and send this powerful pro-inflammatory message,” Ring told Endpoints News. “So we were really intrigued by this paradox that IL-18 had been tried in the clinic and failed and not due to safety concerns but for lack of efficacy.”
The answer, Ring learned, was that decoy receptors around the tumor were soaking up that IL-18, effectively neutering it. Although the decoy receptor is expressed throughout the body, Ring found it was particularly present around cancers. So he and his team developed a decoy for the decoy, a protein that would bind only to IL-18 receptors and not the variant. Ring published the results yesterday in Nature, and with it, announced the launch of a new biotech that, with $25 million in backing, will try to put their new protein into the clinic by next year.
If it holds up, the new protein, called DR-18, could be given with other immunotherapies such as PD-1 inhibitors or CAR-T to enhance their effectiveness. DR-18 could effectively act as a checkpoint therapy for the innate immune system, amping up both natural killer cells and T cells’ ability to attack a tumor. In a review published the same day, Mark Smyth of the QIMR Berghofer Medical Research Institute, said the study had “broad translational implications.”
Sonia Sharma, assistant professor at the La Jolla Institute for Immunology, called the Nature paper “elegant” and “clever” and a “really nice proof of concept” for bringing cytokines back into cancer research. Still, she cautioned there could be serious difficulties moving it from mice to humans.
Cancer treatments that affect the adaptive immune system, such as checkpoint therapies and CAR-T, can cause that system to go into overdrive, sometimes killing tumors but also occasionally leading to dangerous hyper-inflammation. Overstimulating the innate immune system can be even more harmful, she said, because a signal like IL-18 affects a broader range of cells and pathways.
The body makes the decoy molecule — known technically as IL-18BP or IL-18 binding protein — precisely because too much IL-18 can lead to hyperinflammation autoimmune disorders. Severe adverse events have been seen with other interleukins and other drugs that change the innate immune systems, such as STING inhibitors.
“The body’s turning up IL-18BP for a reason,” Sharma told Endpoints. “This is going to hinge on how they deliver this, because infusing a patient with a combination of IL-18 that isn’t sensitive to its natural inhibitor and then combining that with an anti PD-1 might induce serious side effects.”
Ring’s team built DR-18 using a Nobel Prize-winning process called “directed evolution.” Essentially, they made 250 million random genetic variations of IL-18, searching for one that would bind to IL-18 and not IL-18BP. Because the decoy molecule is much better at binding to IL-18 than the actual receptor, they found only 11 different variants that fit the criteria. They whittled those to two, and then, after looking at how each stimulated test-tube natural killer cells, one.
In mice tumors, they found, IL-18 had little effect but DR-18 worked at a “commensurate or superior” rate to PD-1 therapy. When they combined DR-18 and a PD-1 inhibitor, the tumors disappeared in most of the mice. Further analysis showed this happened because of the molecule changing the makeup of T cells around the tumor and re-activating NK cells.
The paper acknowledged the potential for toxicities but said preclinical data found the drug would be well-tolerated.
The new company, called Simcha Therapeutics, will try to advance the drug into the clinic by the first half of 2021. So far, it’s just been Ring and a series of consultants and board members — no employees — but with the new financing, they will now look to fill out a team. Investors included WuXi AppTec’s Corporate Venture Fund, Sequoia Capital China, and Connecticut Innovations.
Although it’s Ring’s first company, it won’t be his first licensed compound. In 2012, as a graduate student, he co-invented an IL-2 drug that’s now in preclinical studies at Medicenna Therapeutics. A year later, he published a CD-47 drug in Science that’s now the lead drug for ALX Oncology.
DR-18 is Simcha’s only asset for now, but Ring said the same techniques could be used to revive a range of other cytokines and immunotherapies that drug companies abandoned because of early biological limitations.
“It’s really an archetype,” he said. “It’s a template for how we would approach other types of cytokines and molecules. Essentially, the idea is we don’t want to accept nature’s solution.”