“What if we could make a version of IL-18 that couldn’t be jammed by the binding protein?” said Dr Ring. “Turns out, this is a really difficult engineering challenge.”

The decoy receptor and the true receptor use completely overlapping binding sites, and the decoy binds 10,000 times more tightly. Designing a molecule that bound to 1 site and not the other was out of the question, and the team turned to directed evolution to solve the problem. They generated nearly 300 million variants of IL-18, each slightly different in the receptor binding site. Then they engineered yeast cells to display the IL-18 variants and applied selection pressure, retaining the variants that bound to the true receptor and discarding those that engaged the decoy. After selection, only a few candidate variants remained that could both link up with the true receptor and ignore the decoy

In mouse models, the decoy-resistant IL-18 (DR-18) inhibited tumor growth and enhanced survival. Significantly, DR-18 acted synergistically with anti–PD-1. Treatment with DR-18 expanded the population of stem-like T-cell precursors that express TCF1, which are needed for a durable immunotherapeutic response.

“There are so many different immunotherapies being tested in the clinic right now, and even though many of them hit different targets, they’re essentially pulling the same lever in a different way,” Dr Ring said. Whereas other immunotherapies consume these stem-like T cells, pushing them toward terminal differentiation, treatment with DR-18 boosted their numbers by 20-fold, he said. “We found that we could synergize with anti–PD-1, and really test a different mechanism in the clinic than other agents that have been tried.”


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In addition, DR-18 also overcame loss of major histocompatibility complex (MHC) class I by boosting natural killer (NK) cell function, possibly opening the door to treatments for tumors previously thought to be poor candidates for immunotherapy. Loss of MHC class I is a common mechanism for tumors to develop resistance to immunotherapy, which no currently available immunotherapies appear to be able to overcome.

“We certainly are going to want to have cohorts of tumors where we can try to make hot tumors hotter; that’s a very important need in cancer,” Dr Ring said. “We also want to look at those cold tumors that are refractory to checkpoint inhibition, particularly those that are resistant due to a loss of antigen presentation that renders them susceptible to NK cells.”

Though tumors exploit the decoy receptor to evade the immune system, the body may need that system in place to keep runaway inflammation in check. Overriding those protections can help get at the tumor, but runs the risk of autoimmune catastrophe.

“There is a possibility that tolerability of conventional IL-18 treatment might be explained by IL-18BP–mediated neutralization,” wrote Kyohei Nakamura, MD, PhD, senior research officer of the QIMR Berghofer Medical Research Institute, Australia, in an email to Cancer Therapy Advisor. Dr Nakamura pointed out that in preclinical studies, overexpression of IL-18 led to liver toxicity, and eliminating IL-18BP caused hyperinflammatory response.3,4 “Thus, dose-limiting toxicities will be carefully studied in clinical trials,” he added.

So far, however, the toxicity data have been promising. Testing in mice, as well as in nonhuman primates, has indicated that DR-18 may have favorable toxicity relative to other cytokines. “Of course, you have to have a high degree of caution and humility when advancing this type of therapy,” said Dr Ring. “These drugs have a lot of promise, but they also have the potential to cause a lot of toxicity, and this is something we’ve been looking at very carefully.”

References

  1. Zhou T, Damsky W, Weizman O-E, et al. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature. 2020;583(7817):609-614. doi:10.1038/s41586-020-2422-6
  2. Tarhini A, Millward M, Mainwaring P, et al. A phase 2, randomized study of SB-485232, rhIL-18, in patients with previously untreated metastatic melanoma. Cancer 2009;115(4):859-868. doi:10.1002/cncr.24100
  3. Finotto S, Siebler J, Hausding M, et al. Severe hepatic injury in interleukin 18 (IL-18) transgenic mice: a key role for IL-18 in regulating hepatocyte apoptosis in vivo. Gut. 2004;53(3):392-400. doi:10.1136/gut.2003.018572
  4. Girard-Guyonvarc’h C, Palomo J, Martin P, et al. Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice. Blood. 2018;131(13):1430-1441. doi:10.1182/blood-2017-06-789552