A phase one trial at the Duke Cancer Institute has revealed promising results for a novel immunotherapy approach in treating glioblastoma, an aggressive form of brain cancer. The study, published in Clinical Cancer Research, evaluated a dendritic cell vaccine in combination with a dose-intensified regimen of temozolomide, a first-line chemotherapy drug. The findings suggest that the combination is well-tolerated and may lead to significant survival gains for patients.
The single-arm study involved 11 patients with glioblastoma who received injections of the investigational vaccine therapy alongside the intensified chemotherapy. Researchers monitored patients for toxicity and adverse events throughout the treatment period. While patients experienced known side effects associated with temozolomide, such as nausea and fatigue, there were no treatment-limiting adverse events directly related to the cellular component of the vaccine. One patient experienced a grade 3 allergic reaction to the GM-CSF component, which was resolved by removing the component from subsequent vaccinations.
Survival Outcomes
Although the trial was primarily designed to assess safety, the survival outcomes were notable. Four of the 11 patients survived for more than five years following treatment. This is a significant improvement compared to the median survival of approximately 15 months typically observed with the current standard of care for glioblastoma.
"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 Kristen Batich, M.D., Ph.D., lead author from Duke University. "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."
Targeting CMV Proteins
The dendritic cell vaccine used in the study targets a cytomegalovirus (CMV) protein, which is abundant in glioblastoma tumors but absent in surrounding brain cells. The vaccine is designed to teach T-cells to attack tumor cells expressing this protein. Previous trials have suggested that the vaccine's efficacy can be enhanced when primed by an immune system booster, and that higher doses of temozolomide can also prime the immune system.
Exploiting Temozolomide-Induced Lymphopenia
The researchers combined the dendritic cell vaccine therapy with an immune-stimulating factor, administering it after dose-intensified regimens of temozolomide. The rationale behind this approach is to capitalize on the immune deficiency caused by temozolomide.
"Our strategy was to capitalize on the immune deficiency caused by the temozolomide regimen," Batich explained. "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."
Impact on Tumor Progression
The treatment also appeared to slow the progression of tumors. Typically, glioblastoma tumors begin to regrow after standard treatment at a median of eight months. However, in the study participants, recurrence occurred at a median of 25 months.
Future Directions
"These are surprisingly promising clinical outcomes," said John Sampson, M.D., Ph.D., chair of Duke’s Department of Neurosurgery and senior author of the study. "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 comparing the standard dose of temozolomide versus the dose-intensified regimen along with the vaccine in glioblastoma patients. This upcoming trial will provide further insights into the efficacy of this novel immunotherapy approach.
