Nick Mulcahy

April 12, 2013

WASHINGTON, DC — Two of the hottest treatment approaches in oncology — immunotherapy and antibody–drug conjugates — offer the promise of improved outcomes in difficult-to-treat advanced ovarian cancer, according to 2 studies presentations here at the American Association for Cancer Research 104th Annual Meeting.

The immunotherapy for ovarian cancer is actually a 2-step process, which, for the first time ever, combines dendritic cell vaccination and adoptive T-cell therapy, said Lana Kandalaft, PharmD, PhD, from the Ovarian Cancer Research Center in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

In a phase 1 trial, 20 of 31 patients (66%) with stage III/IV ovarian cancer who were treated with the first step (vaccine alone) had either stable disease (n = 17) or partial response (n = 3). Bevacizumab (Avastin, Roche/Genentech) was administered during both treatment steps.

The 11 patients who received the vaccine but still had residual disease moved on to the second step (immunotherapy), an adoptive T-cell therapy. Of this group, 73% experienced benefit; 7 patients had stable disease and 1 had a complete response.

This clinical trial has had one especially dramatic result, said Dr. Kandalaft during a meeting press briefing. A patient who had 2 recurrences and had undergone debulking surgeries received the vaccine alone (step 1) and has had 45 months of progression-free survival.

Advanced ovarian cancer represents an area of huge unmet medical need, said Dr. Kandalaft.

"Most patients with ovarian cancer are diagnosed at an advanced stage; many of those relapse within 2 years and most die within 5 years. Given these grim outcomes, there is definitely a vast unmet need for the development of novel, alternate therapies," she said in a press statement.

The 2-step treatment process used in this study was developed at the Penn Ovarian Cancer Research Center.

First, a vaccine is prepared by exposing immune cells, known as dendritic cells, isolated from the blood of each patient, to her own tumor tissue, which was collected during debulking surgery. The vaccine is delivered in a series of 5 injections over a 3-month period.

Second, T-cells, now "vaccine primed," were removed from the patient's blood. Laboratory processes are used to stimulate and expand these immune cells, which are then reinjected into the patient.

In the 2-step process, the dendritic cells act as "spies" and collect information about targets. The spies return to the lymph nodes — the "headquarters" — where they inform the T-cells — the "soldiers" — which then go and "combat the tumor," Dr. Kandalaft explained.

In effect, the second step of the process, the adoptive transfer of T-cells, amplifies the antitumor immune response. This is explains why there were more patients with stable disease/responders in the group that underwent both steps than in the group that underwent only the first step (73% vs 66%).

Antibody–Drug Conjugate for Platinum-Resistant Disease

At the same press briefing, another investigator presented results from a phase 1 study of an experimental agent that targets ovarian tumors expressing the MUC16 protein.

Eighty percent of all ovarian cancers express the MUC16 protein, said lead author Joyce F. Liu, MD, MPH, from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

The new agent, known as DMUC5754A (Roche/Genentech), is an antibody–drug conjugate, which is a new class of drug, the best known of which is trastuzumab emtansine or T-DM1 (Kadcyla, Roche/Genentech), used in metastatic HER2-positive breast cancer.

In the first-in-human trial, more than 20% of 44 patients with advanced, recurrent, platinum-resistant ovarian cancer experienced a response to DMUC5754A, Dr. Liu reported.

Among the study participants, there was 1 complete response and 4 partial responses (more than 30% shrinkage of tumor). All 5 of these responses occurred in patients whose cancer cells expressed high levels of MUC16 and who were treated with the 2.4 mg/kg dose.

DMUC5754A is a combination of an antibody and a potent toxin. The antibody identifies a protein, MUC16, which is highly expressed in ovarian cancers, and targets the toxin to kill the cancer cells. The antibody–drug conjugate releases the toxin with relative selectivity to MUC16-positive cancer cells. This allows delivery of drugs that would otherwise be too toxic for treatment, according to Dr. Liu.

"If the activity of this drug is confirmed in additional trials, this will represent a novel type of therapy for ovarian cancer that is quite difficult to treat," she noted.

Current therapies for platinum-resistant ovarian cancer are "limited in their effectiveness and typically short lived," she told reporters.

The women in the trial were heavily pretreated; they received an average of 7 previous chemotherapy treatments.

The agent has "an acceptable safety profile," said Dr. Liu.

During the study, 2 dose-limiting toxicities occurred: 1 case of grade 4 neutropenia and 1 case of grade 4 uric acid increase, which occurred at the maximum administered dose of 3.2 mg/kg. Grade 3 adverse events included fatigue in 9% of patients and neutropenia in 9% of patients.

Fatigue was the most common grade 3/4 adverse event at all dose levels. Overall, fatigue occurred in 57% of patients. Other commonly reported adverse events were nausea, vomiting, decreased appetite, diarrhea, and peripheral neuropathy.

The results seen with DMUC5754A demonstrate that antibody–drug conjugates are the real deal as a class of drug, and that T-DM1 is "not a one-off example of a drug that works," said Louis Weiner, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who moderated the press briefing.

"This is a therapeutic concept that matters and makes sense. You can take an antibody that will target an important antigen on a tumor cell surface. You can deliver a cytotoxic poison to the interior of that cell...kill it, and make people's cancers get better," he said.

Dr. Kandalaft 's immunotherapy study was funded by a National Cancer Institute Ovarian Specialized Program of Research Excellence grant, the National Institutes of Health, and the Ovarian Cancer Immunotherapy Initiative. Dr. Kandalaft and Dr. Liu have disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 104th Annual Meeting: Abstracts LB-335, presented April 10, 2013; Abstract LB-290, presented April 9, 2013.


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