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IL-15 Prepares for Its Clinical Debut

It’s been nearly two decades since CCR researcher Thomas Waldmann, M.D., co-discovered interleukin-15 (IL-15), a cytokine and potent stimulator of antitumor memory CD8+ T cells. Now, in a major step towards the molecule’s clinical development, Waldmann—Chief of CCR’s Metabolism Branch—and his CCR colleagues have started the process of testing IL-15 in human cancer patients for the first time.

It took several years and a major collaboration at the NIH between NCI and the National Institute of Allergy and Infectious Diseases (NIAID) to produce clinical-grade IL-15 for human cancer research. “This is a watershed moment,” Waldmann said. “IL-15 is one of the most promising new candidates in cancer immunotherapy. For us to have reached this point is hugely gratifying, considering the long scientific odyssey that might never have happened without the cooperation of CCR’s Robert Wiltrout, Ph.D., and Clifford Lane, M.D., Deputy Director for Clinical Research and Special Projects at NIAID.”

The IL-15 being used by Waldmann was produced by NCI’s Biopharmaceutical Development Program (BDP), part of the Division of Cancer Treatment and Diagnosis (DCTD). During a series of NCI-sponsored workshops, investigators put IL-15 at the top of a list of the most compelling new immunotherapies for cancer treatment. The Cancer Immunotherapy Trials Network (CITN), a newly organized multicenter research consortium funded by NCI and headquartered at the Fred Hutchinson Cancer Research Center in Seattle, Wash., has made IL-15 studies a priority. In addition to Waldmann and Lane, other investigators are beginning clinical research with IL-15 including Steven Rosenberg, M.D., Ph.D., Chief of CCR’s Surgery Branch, and a number of extramural scientists, including Jeffery Miller, M.D., the Associate Director of Experimental Therapeutics at the Masonic Cancer Center, University of Minnesota.

“IL-15 holds great promise for exploiting the immune system to treat cancer and infectious diseases,” said Wiltrout. “The ability to fully understand its possible benefits to patients has been limited by a lack of commitment from the private sector to develop it for clinical use. Thus, the decision by NCI’s CCR and DCTD to partner with NIAID has now resulted in the production of clinical grade IL-15 and the initiation of novel clinical trials that would otherwise not have been possible.”

Potentially Better Than IL-2

Much of the excitement surrounding IL-15 concerns its ability to stimulate natural killer (NK) and CD8+ T cells without inducing capillary leak syndrome. This reaction, typically associated with a related immunotherapy in clinical use today—IL-2—heightens the risk for organ failure in some patients. What’s more, unlike IL-2, IL-15 doesn’t trigger regulatory T cells (Tregs or suppressor cells) that might otherwise put the brakes on its therapeutic benefits.

Waldmann co-discovered IL-15 in 1994, at about the same time that Kenneth Grabstein, Ph.D., a scientist with Immunex Research and Development Corporation, in Seattle, Wash., was making the same discovery. Working independently, the scientists found that IL-2 shares its T cell receptor with a related molecule—later called IL-15—with which it has some similarities, but also some important differences. Both IL-2 and IL-15 stimulate T cell proliferation, activate NK cells, and induce immunoglobulin synthesis by human B cells. However, unlike IL-15, IL-2 also participates in activation-induced cell death (AICD) of helper CD4+ T cells, is critical in the maintenance of Tregs, and blocks the persistence of memory CD8+ cells. According to Waldmann, this is how IL-2 helps to eliminate lymphocytes that target self-antigens in autoimmune illness. IL-15, on the other hand, inhibits IL-2’s role in AICD, has a positive effect on memory CD8+ cells, and, therefore, favors long-term responses against foreign pathogens.

“So we postulated that IL-15 might be useful for cancer treatment,” Waldmann said. “And we and others were able to demonstrate this in a number of mouse models, while also showing that IL-15 had relatively low toxicity. This is what convinced NCI to stimulate funding for the production of clinical-grade IL-15 for further research.”

The IL-15 subsequently produced by the BDP (in an E. coli expression system) under the direction of Stephen Creekmore, M.D., Ph.D., Chief of NCI’s Biological Resources Branch, was then tested in a primate model through a collaborative project involving scientists throughout the NIH. Results published in the journal Blood, on May 5, 2011, confirmed what Waldmann and other researchers saw in mouse models: Given by bolus infusion, at doses ranging from 10-50 μg/kg/day for 12 days, IL-15 stimulated NK and memory CD8+ cells with minimal toxicity. Buoyed by these findings, Waldmann and co-authors submitted 2,700 pages of supporting data to the Food and Drug Administration (FDA), along with their Investigational New Drug Application to sponsor a clinical trial in humans with metastatic cancer.