Nancy A. Melville

May 12, 2016

CHICAGO — A novel combination of a cytomegalovirus (CMV)-targeted dendritic cell vaccine administered after preconditioning with a tetanus booster in the treatment of glioblastoma brain tumors shows significant improvement in overall survival, according to results from phase 2 clinical trials.

"CMV pp65-DC vaccines are associated with superior overall survival now in multiple trials, fortifying the rationale for CMV targeting and long-term survival in other studies," said first author Kristen A. Batich, an MD candidate in the Division of Neurosurgery at Duke University Medical Center, Durham, North Carolina.

The findings were presented here at the American Association of Neurological Surgeons (AANS) 84th Annual Meeting.

In research http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14320.html?message-global=remove published last year in Nature, Batich and colleagues initially described survival data from the double-blinded ATTAC trial, a small but encouraging study involving 12 patients with glioblastoma.

The patients were randomly assigned to treatment with the dendritic cell vaccine, targeting the CMV antigen pp65, along with vaccine site preconditioning with tetanus-diphtheria toxoid booster, or with unpulsed dendritic cells. All patients also received standard radiation and temozolomide (TMZ) 200 mg/m2 for 5 days.

In that trial, half of the patients in the nontetanus group survived to 11.6 months from the time of the vaccine site preconditioning and to 18.5 months from the time of diagnosis at surgery, Batich explained.

"This is still greater than the expected survival with current standard of care," which has a median survival of approximately 14.6 months, she told Medscape Medical News.

Patients randomly assigned to receive the pp65 targeted dendritic cells combined with the tetanus preconditioning showed a much better response, however, surviving from 57.2 to 120.4 months, substantially longer than the nontetanus group, and three of the six patients in the tetanus-conditioning group were still alive at the time of survival analysis.

Remarkably, "one patient from the tetanus group continues to have no tumor growth and is still alive at 120.4 months or 10 years after the treatment," Batich told Medscape Medical News.

For the subsequent single-arm phase 2 ATTAC-GM trial, 11 patients were treated with dose-intensified TMZ (100 mg/m2 for 21 days) and radiation, along with the dendritic cell vaccine targeting pp65 and tetanus preconditioning.

In the second trial, patients further showed significant increases in pp65 dendritic cell responses (P = .0186), with immunogenicity assessed with pp65-specific ELISpot.

The second trial also showed significant increases in median progression-free survival (25.3 months) and overall survival (41.1 months).

Among the 11 patients, 4 were progression-free at the time of the survival analysis, at 59 to 64 months after their diagnosis.

Batich said the researchers are still trying to determine whether the survival benefit is related more to the targeting of the CMV antigens or the tetanus precondition — or both.

"The survival benefit could possibly result from both therapies — of course, the first ATTAC trial was a small randomized trial of only 12 patients (6 and 6 per arm)."

"Interestingly, patients receiving the tetanus before the CMV vaccine seemed to have much longer survival," she added. "This may be related to the ability of tetanus to improve the migration of the CMV dendritic cell vaccine to local lymph nodes."

"All in all, the contributions of either CMV targeting and tetanus with DC [dendritic cell] vaccines would have to be studied in a higher-powered trial with a great sample size."

Importantly, the CMV-targeting vaccine shows a good safety profile.

"One of the advantages of an immunotherapy vaccine like CMV-DCs is precisely the quality of life for patients," Batich explained.

"Other than getting the vaccine itself, which may cause some soreness and local swelling much like a tetanus or flu shot, there are essentially no side effects."

"The vaccine contains the patients' own cells that are educated to go and target CMV proteins in the body, so it is very specific," she said.

The researchers are continuing the ongoing open phase 2 trial, replicating the design of the ATTAC trial for patients with newly diagnosed glioblastoma.

"This study is higher-powered for the questions we would like to answer on the contribution of tetanus in improving DC vaccines as well as validate the targeting of CMV pp65 protein within the brain tumors," Batich said.

Batich and coauthors hold patents related to technologies described in the study. The research was funded in part through a National Institutes of Health (NIH) STTR phase I grant to Annias Immunotherapeutics, a Duke start-up venture, presently finalizing an exclusive license to the technology. The study also received funding from grants from the National Institute of Neurological Disorders and Stroke, a unit of the NIH, and from the NIH, the American Brain Tumor Association, the National Brain Tumor Society, the Accelerate Brain Cancer Cure Foundation, the Kinetics Foundation, the Ben and Catherine Ivy Foundation, and in part by Duke University's Clinical & Translational Science Awards grant 1UL2 RR024128-01 from the NIH National Center for Research Resources.

American Association of Neurological Surgeons (AANS) 84th Annual Meeting. Abstract 701. Presented May 3, 2016.

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