Trials Show Delayed Recurrence in Ovarian Cancer

Phase I studies of a 2-step immunotherapy treatment and an antibody–drug conjugate give encouraging results.

More than 22,000 women are diagnosed with ovarian cancer in the United States each year, and about 16,000 die from it. Phase I trials of 2 alternatives to standard platinum-based chemotherapy, a 2-step immunotherapy treatment and an antibody–drug conjugate (ADC), demonstrated promising early results in delaying recurrence of the disease. The findings were presented at the American Association for Cancer Research (AACR) Annual Meeting 2013 in Washington, DC, April 6–10.

The 2-step immunotherapy treatment combined a dendritic-cell-based autologous vaccine with adoptive T-cell therapy, says Lana Kandalaft, PharmD, PhD, assistant professor and director of clinical development and operations at the Ovarian Cancer Research Center in the Perelman School of Medicine at the University of Pennsylvania (UPenn) in Philadelphia.

In the first step, among 31 patients with recurrent, progressive ovarian cancer who were given the vaccine, 19 showed clinical benefit, including 8 with no measurable disease at the end of the study—one of whom remained disease-free for 42 months after treatment. Another 11 patients who achieved clinical benefit but showed residual disease moved on to the second step of adoptive T-cell therapy, receiving vaccine-primed CD3/CD8-costimulated peripheral blood T cells. Among this subset, 7 had stable disease and 1 had a complete response.

UPenn modified its vaccine platform after the first 6 patients received it. To aid immune response, those 6 patients were first primed with bevacizumab (Avastin; Genentech) and cyclophosphamide. They were then given multiple intradermal injections of an autologous vaccine that was made by pulsing dendritic cells with supernatant tumor lysate.

The remaining 25 patients were given an optimized vaccine based on work showing improved survival in mice. After priming with bevacizumab, the patients were given multiple intranodal injections of a vaccine combining dendritic cells with hydrochloric-acid-oxidized whole-tumor lysate. Using whole-tumor lysate rather than lysate supernatant presents more molecular targets for the vaccine, Kandalaft explains, while the hydrochloric acid helps to activate the dendritic cells.

Moving forward, the researchers plan to add aspirin to the mix, in the hope that this, like bevacizumab, may open up the tumor environment for increased penetration by dendritic cells, Kandalaft says. “The immunosuppressive environment that the tumor creates around itself will always work against you, and we need to try to fix it,” she notes.

“The vaccines are not powerful enough to melt huge lesions, at least for now,” she remarks. “Patients who have no evidence of disease or very small-volume disease will benefit most. If you can catch the patients early enough in the disease, you may really prolong this preventive action.”

Kandalaft suggests that the vaccine eventually may also prove useful for post-surgical “watchful waiting” periods when patients are not taking medication. “These patients have no side effects; they get the vaccine injection and go out and walk in the park,” she adds.

Another therapy, Genentech's ADC DMUC5754A, also demonstrated favorable early results, in a phase I trial among 44 patients with platinum-resistant ovarian cancer.

Among 29 of those patients who were given a maximum-tolerated dose, “we definitely saw positive signs of activity, with 4 partial responses and 1 complete response,” says Joyce Liu, MD, MPH, an instructor in medicine at Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA. “It's a very promising signal in a population that is quite resistant to traditional chemotherapy.”

On the safety side, the most common adverse events among all patients in the trial were fatigue (57%), nausea (34%), vomiting (27%), decreased appetite (25%), peripheral neuropathy (25%), and diarrhea (23%). “Our feeling is that this is quite a tolerable regimen; patients did have these adverse events, but they were manageable, and they stayed on treatment for prolonged periods,” Liu says.

DMUC5754A targets the MUC16 transmembrane protein, which is highly expressed in about 80% of ovarian cancers. “When it's cleaved, the extracellular component is released into the blood as CA125, a well-established ovarian cancer biomarker,” she says.

The ADC incorporates an antibody that targets a domain with tandem repeats on the extracellular portion of MUC16. This antibody is combined with a protease-cleavable peptide linker and the microtubule-disrupting cytotoxic monomethyl auristatin E (MMAE). After binding to MUC16 on the surface of a tumor cell, the ADC is rapidly internalized and releases MMAE to kill the cell.

“We're still completing our analysis of phase I results, but this certainly has the criteria we like to see in phase I to move it into a next-stage trial,” says Stuart Lutzker, MD, PhD, vice president of BioOncology Exploratory Clinical Development at Genentech in San Francisco, CA. “We expect that an ADC should shrink tumors, and that's what we report in this trial. The safety is as we would expect from our preclinical study; it's a very tolerable drug at the dose we would utilize in next-phase studies.”

Response to the drug closely tracks expression of MUC16, potentially supporting the use of a companion diagnostic, Lutzker emphasizes.

In February, the U.S. Food and Drug Administration approved Genentech's ADC Kadcyla (also known as ado-trastuzumab emtansine or T-DM1) for HER2-positive metastatic breast cancer. “That has engendered a fair amount of enthusiasm for the ADC field in general,” Lutzker comments. “ADCs can be both safer and more effective than standard chemotherapies. We would like to see ADCs replace chemotherapy and then become the backbone to which other therapies are added.” –Eric Bender