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First-in-Humans Study of New Immunotherapy Agent

Name of the Trial

Phase I Study of Intravenous Recombinant Human IL-15 in Adults with Refractory Metastatic Malignant Melanoma and Metastatic Renal Cell Cancer (NCI-10-C-0021). See the protocol summary.

Principal Investigators

Dr. Thomas Waldmann and Dr. Kevin Conlon (Associate Investigator), NCI Center for Cancer Research   

Drs Thomas Waldmann and Dr. Kevin Conlon
Dr. Thomas Waldmann and Dr. Kevin Conlon
Principal Investigators

Why This Trial Is Important

The goal of cancer immunotherapy is to stimulate or restore the ability of the body’s immune system to attack cancer cells. Although some evaluated treatments have demonstrated an ability to help boost or activate immune responses against cancer cells, immunotherapy is still a relatively new area of cancer research and much remains to be learned. For example, researchers need to learn how best to incorporate immunotherapy in cancer treatment strategies, which cancers are most susceptible to immune system manipulation, and how to reduce or avoid serious side effects.

The immunotherapy agent interleukin-2 (also called IL-2 or aldesleukin) has been approved by the FDA for the treatment of metastatic melanoma and metastatic renal cell carcinoma, the most common type of kidney cancer. IL-2 is a type of cytokine, a naturally occurring protein that helps regulate immune responses.

Despite its anticancer activity in some patients, IL-2 therapy has several drawbacks. IL-2 plays a dual role in the immune system by 1) stimulating the proliferation of cells that can attack and kill pathogens, including cancer cells, and 2) suppressing immune responses to keep the immune system from attacking the body’s normal cells (autoimmune responses). As a result, IL-2’s stimulation of cancer-killing cells, such as cytotoxic T cells and natural killer (NK) cells, fades rather quickly, necessitating the use of high doses of IL-2 to be effective.

However, high doses of IL-2 often produce serious side effects that may adversely affect a patient’s quality of life, compromise treatment, or even result in the patient’s death. Therefore, doctors are eager to identify other immunotherapy agents that provide benefits similar to IL-2 but with fewer drawbacks.

Another member of the interleukin family, interleukin 15 (IL-15), may be one possibility. In preclinical studies, IL-15 has been shown to stimulate many of the same immune cells as IL-2 but with much longer-lasting effects. Unlike IL-2, it does not act to suppress immune responses. IL-15 also stimulates the proliferation of immune cells that have a “memory” of the cancer, so the immune system can recognize and attack the cancer again, possibly enabling it to head off recurrences. Furthermore, animal studies with IL-15 suggest that it may also have a better side effect profile than IL-2.

“Both IL-2 and IL-15 stimulate T cells and B cells, and they are involved in the generation of natural killer cells, but they are clearly different,” said Dr. Waldmann, who co-discovered IL-15 in 1994. IL-2 prevents autoimmunity, explained Dr. Waldmann. IL-15, in contrast, produces an immune response of very long duration.

“In studies with nonhuman primates, we’ve seen natural killer cells increase sevenfold and cytotoxic T cells increase 80- to 100-fold following administration of IL-15 as a 10-day continuous infusion. So [in IL-15] we have an agent that is a superstimulator of natural killer cells and cytotoxic T cells,” he explained.

Laboratory and animal testing with IL-15 has generated a great deal of interest in bringing the agent to clinical testing in cancer patients. In fact, immunotherapy experts participating in the NCI Immunotherapy Agent Workshop in 2007 ranked IL-15 as the most important agent to bring to clinical trials.

 “Researchers have been waiting a long time for clinical grade IL-15, but pharmaceutical companies have largely gotten out of the business of producing new cytokines following some early clinical disappointments [with immunotherapy],” said Dr. Conlon. “So, NCI has invested in developing and producing the agent through its Developmental Therapeutics Program to allow clinical testing of this very highly anticipated cytokine to proceed.”

In this first-in-humans study of IL-15, patients with metastatic melanoma or metastatic renal cell cancer who have not benefited from other therapies will be given IL-15 by intravenous injection once a day for 12 days. Doctors will assess the tolerability of IL-15 therapy in the patients and determine the maximum tolerated dose and dose-limiting toxicities.

“We’re currently in the process of planning additional studies of IL-15, using different routes of administration so that we can better inform future phase II monotherapy and combination studies to be conducted through the new Cancer Immunotherapy Trials Network and by other extramural and intramural researchers,” Dr. Conlon added.

For More Information

See the lists of eligibility criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

  • Posted: January 24, 2012