Study may show new option for ovarian cancer patients

Adam Karpf, Ph.D.

A study by UNMC and Roswell Park Cancer Institute shows that a combination treatment strategy may provide a new option for patients with recurrent ovarian cancer.

The study, published in Cancer Immunology Research, found clinical benefit for women who were treated with the drug decitabine prior to administration of chemotherapy and a cancer vaccine.

“We’re encouraged by the results from the phase I clinical study and look forward to extending this concept to the phase II setting, where treatment efficacy is the principal end point,” said Adam Karpf, Ph.D., associate professor, Eppley Institute, and member, Fred & Pamela Buffett Cancer Center, at UNMC.

A prerequisite for the immune system to recognize and attack a tumor is the presence of high levels of a protein not normally found in healthy cells. Proteins with this profile are called tumor antigens and can be good targets for anticancer vaccines.

Phase II Dr. Karpf’s co-principal investigator was Kunle Odunsi, M.D., Ph.D., professor and chair of the department of gynecologic oncology and director of the Center for Immunotherapy at Roswell Park Cancer Institute, Buffalo, N.Y. Based on the encouraging findings of the Phase I trial, the investigators are planning a Phase II trial at UNMC and Roswell Park to specifically evaluate the clinical efficacy of this novel chemo-immunotherapy approach in patients with recurrent ovarian cancer. For the original study, see Cancer Immunology Research 2014; 2:37-49. The study was funded by the National Cancer Institute, the Ovarian Cancer Research Fund, the Roswell Park Alliance Foundation, a Cancer Vaccine Collaborative Grant, the Anna Maria Kellen Clinical Investigator Award, and Eisai Pharmaceuticals. Drs. Karpf and Odunsi have declared no conflicts of interest.

“Preclinical studies by our group have shown that a specific class of tumor antigens is regulated by DNA methylation,” Dr. Karpf said. “Based on this knowledge, we developed the new clinical regimen.”

The investigators conducted a phase I dose-escalation trial of the DNA methyltransferase inhibitor decitabine, recruiting 12 women with epithelial ovarian cancer who had not responded to multiple lines of chemotherapy, with an estimated progression-free survival time of three months. Patients received decitabine on day one, the chemotherapy drug doxorubicin on day eight, and the cancer vaccine on day 15.

The investigators established the best sequence of drug administration: decitabine was effective only when administered before chemotherapy; it was ineffective if given after chemotherapy; vaccine administration was the last step.

Of the 10 patients evaluated, five had stable disease for up to 7.8 months, and one had a partial response with disease remission that lasted 5.8 months.

The dose escalation data suggested that lower doses of decitabine are associated with improved clinical response using this regimen. The treatment was well tolerated, and adverse events included hematologic side effects that were clinically manageable.

One remarkable result was that the therapeutic regimen led to a phenomenon called “antigen spreading,” Dr. Karpf said. “Although we immunized against a single antigen, we found induction of immune responses against an additional three antigens. We believe this may have resulted from the decitabine treatment.”

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