In one of the most encouraging cancer vaccine therapy trials to date, researchers from the University of Chicago and Genetics Institute (Cambridge, MA) have demonstrated that their faster, simpler and safer approach to treatment may also be more effective than previous cancer vaccines. By giving melanoma patients the immune stimulant interleukin-12, the researchers were able to bypass the costly and difficult process of growing large populations of dendritic cells in culture and returning them to the patient, a process that takes weeks.
Instead, they extracted circulating white blood cells, exposed them to either of two markers commonly seen on melanoma cells, and returned them to the patient -- a process that takes only a few hours. Then they gave the patients different doses of IL-12 over the next five days to boost the immune response. The treatment cycle was repeated three times.
"Using total white blood cells instead of cultured dendritic cells was somewhat heretical," explains Thomas Gajewski, M.D., Ph.D., assistant professor of pathology and medicine at the University of Chicago and director of the study, "but our results indicate that it can be just as effective yet avoids the risks, delays and complexity associated with growing dendritic cells in culture."
The key finding, presented May 17th at the annual meeting of the American Society of Clinical Oncology in Atlanta, was the surprise discovery that moderate doses of IL-12 were far more effective at stimulating an anti-cancer response than higher, more-toxic doses.
Phase-1 clinical trials are usually designed to determine the maximum tolerated dose of a new drug, but this trial indicated that the best dose was about one tenth of the maximum dose -- suggesting that dosing trials of biologic therapies require a radically different design. At moderate doses, IL-12's most serious side effects were tenderness at the injection site, tiredness and mild fever. Higher doses were more toxic and much less effective.
In addition to generating few side effects at low-to-moderate doses, the regimen was unusually effective. Fifteen patients were enrolled, all with advanced melanoma. Fourteen had previously gotten worse despite prior treatments including chemotherapy, radiation therapy and biologic therapy (with interferon or IL-2). The other patient had not had prior therapy.
Six of the eight patients who received the optimal IL-12 dose had significant benefit. One patient with multiple metastatic tumors in both lungs had a complete response and has been disease free for more than a year.
In two other patients, the tumors decreased in size and have remained stable for more than a year. Three patients had some of their tumors shrink and other tumors -- which lacked the markers targeted by the vaccine -- continue to grow.
Despite a life expectancy of three-to-nine months when enrolled, patients with a complete or partial response are alive more than 15 months later.
"Although only small numbers of patients have been treated so far, these outcomes should increase enthusiasm for further development of vaccine-based therapies," said Gajewski. "Many investigators were starting to give up on vaccines as a treatment tool for metastatic disease and to focus instead on vaccines that might prevent recurrence for patients already in remission. We now think this approach, once optimized,can have a beneficial effect even on advanced melanoma."