Cytomegalovirus Targeted Vaccination Increases Survival In Glioblastoma

Injections of an investigational vaccine therapy and an approved chemotherapy have been demonstrated to be well tolerated and result in unexpectedly significant survival increases in glioblastoma patients, Duke Cancer Institute researchers report.

Even though the phase one trial was small and not designed to evaluate efficacy, four of the 11 study patients survived for more than five years following treatment with a combination of vaccine and the drug temozolomide, a first-line chemotherapy drug for glioblastoma. That outcome is uncommon for glioblastoma, a lethal brain cancer that has a median survival of nearly 15 months when treated with the current standard of care.

Lead author Kristen Batich, M.D., Ph.D., said:

“This is a small study, but it’s one in a sequence of clinical trials we have conducted to explore the use of an immunotherapy that specifically targets a protein on glioblastoma tumors. While not a controlled efficacy study, the survival results were surprising, and they suggest the possibility that combining the vaccine with a more intense regimen of this chemotherapy promotes a strong cooperative benefit.”

Temozolomide Plus CMV Vaccine

Batich and colleagues — including senior author John Sampson, M.D., Ph.D., chair of Duke’s Department of Neurosurgery — treated 11 patients as part of a single arm study to test the safety of using a dose-intensified regimen of temozolomide along with a dendritic cell vaccine therapy that selectively targets a cytomegalovirus (CMV) protein. CMV proteins are abundant in glioblastoma tumors, but are absent in surrounding brain cells.

Kristen Batich

John Sampson, M.D., Ph.D., chair of Duke’s Department of Neurosurgery, works with lead author Kristen Batich, M.D., Ph.D., on a previous study in this file photo from Duke Health. Credit: Shawn Rocco, Duke Health

Patients treated with dose-intensified temozolomide plus vaccines were continuously monitored for toxicity and adverse events. Study patients experienced known side effects with temozolomide, including nausea, lymphopenia, thrombocytopenia and fatigue.

In earlier clinical trials, the researchers used the dendritic cell vaccine to teach T-cells to attack tumor cells, and their data suggested these vaccines could be enhanced when primed by an immune system booster. A separate clinical trial found that higher-than-standard doses of temozolomide, combined with an immune-stimulating factor, also primed the immune system and enhanced the response of a different vaccine target.

Depleted Lymphocytes

The researchers built on those findings in the current study. They used a combination of the dendritic cell vaccine therapy and the immune-stimulating factor, which was administered as injections following dose-intensified regimens of temozolomide. The 11 patients received at least six vaccine treatments.

“Our strategy was to capitalize on the immune deficiency caused by the temozolomide regimen,” Batich said. “It seems counter-intuitive, but when the patient’s lymphocytes are depleted, it’s actually an optimal time to introduce the vaccine therapy. It basically gives the immune system marching orders to mount resources to attack the tumor.”

Batich said the approach significantly slowed the progression of patients’ tumors. Typically, glioblastoma tumors begin to regrow after standard treatment at a median of eight months, but for study participants, recurrence occurred at a median of 25 months.

The research team has received approval to launch a new study that will compare the standard dose of temozolomide vs. the dose-intensified regimen along with the vaccine in glioblastoma patients.

Kristen A. Batich, Elizabeth A. Reap, Gary E. Archer, Luis Sanchez-Perez, Smita K. Nair, Robert J. Schmittling, Pam Norberg, Weihua Xie, James E. Herndon II, Patrick Healy, Roger E. McLendon, Allan H. Friedman, Henry S. Friedman, Darell Bigner, Gordana Vlahovic, Duane A. Mitchell and John H. Sampson
Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination
Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-16-2057

Top Image: Brain scans are from glioblastoma trial from manuscript. Credit: Clinical Cancer Research/American Association for Cancer Research

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