Duke: A phase one study of 11 patients with glioblastoma who received injections of an investigational vaccine therapy and an approved chemotherapy showed the combination to be well tolerated while also resulting in unexpectedly significant survival increases, researchers at the Duke Cancer Institute report. Patients treated with the study drug (dose-intensified temozolomide and vaccines) were continuously monitored for toxicity and adverse events. Study patients experienced known side effects with temozolomide, including nausea, lymphopenia, thrombocytopenia and fatigue. There were no treatment limiting adverse events and no adverse events related to the cellular portion of the vaccine. One patient developed a grade 3 vaccine-related allergic reaction to the GM-CSF component of the vaccine. The patient was able to continue vaccinations in which the GM-CSF was removed and had no subsequent adverse events.
Although the 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.
“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,” said Duke’s
Kristen Batich, M.D., Ph.D., lead author of a study published online
April 14 in the journal Clinical Cancer Research.
“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
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.
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
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.
“These are surprisingly promising clinical outcomes,” Sampson said.
“However, it is important to emphasize that this was a very small study
that used historical comparisons rather than randomizing patients to two
different treatments, but the findings certainly support further study
of this approach in larger, controlled clinical trials.”
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.
In addition to Sampson and Batich, study authors include Elizabeth A.
Reap, Gary E. Archer, Luis Sanchez-Perez, Smita K. Nair, Robert J.
Schmittling, Pam Norberg, Weihua Xie,
James E. Herndon, Patrick Healy, Roger E. McLendon, Allan H.
Friedman, Henry S. Friedman, Darell Bigner, Gordana Vlahovic and Duane