Cytomegalovirus targeted vaccination plus high-dose chemotherapy with temozolomide can lead to long-term progression-free and overall survival in patients with newly diagnosed glioblastoma.
Cytomegalovirus (CMV)-targeted vaccination plus high-dose chemotherapy with temozolomide can lead to long-term progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed glioblastoma (GBM), according to a new study published in Clinical Care Research.
Despite surgical resection, high-dose radiation, and chemotherapy with temozolomide, GBM patients typically survive a median of 15 months. CMV proteins are expressed in more than 90% of GBM. “Recent evidence has also demonstrated that CMV-specific T-cell immunity can be generated to recognize and effectively kill autologous GBM tumor cells expressing endogenous levels of the immunodominant pp65 antigen, providing compelling support for the development of CMV-directed immunotherapy for the treatment of GBM,” stated the researchers, led by Kristen A. Batich, MD, PhD, a researcher in the departments of neurosurgery and pathology at Duke University Medical Center in Durham, North Carolina.
Building on previous research, the researchers used CMV as a proxy for GBM, targeting the virus with pp65-specific dendritic cells to spotlight the tumor for the immune system. Following the standard of care, 11 patients with newly diagnosed GBM received dose-intensified temozolomide 100 mg/m2 daily for 21 days per cycle with at least 3 vaccines of pp65 lysosome–associated membrane glycoprotein mRNA-pulsed dendritic cells admixed with granulocyte macrophage colony-stimulating factor (GM-CSF) on day 23 of each cycle.
All 11 patients received at least 7 vaccines of pp65-dendritic cells. The median PFS was 25.3 months and median OS was 41.1 months. Four patients who received at least 3 vaccinations remained progression-free for 59 to 64 months. “The clinical outcomes in GBM patients who received this combination were very striking,” said the researchers, with patient survival far exceeding that of predicted outcomes and observed rates in historical controls.
Prognostic factors, including age, Karnofsky performance status, IDH-1/2 mutations, and MGMT promoter methylation, did not predict more favorable outcomes.
A prior clinical study by the same researchers had demonstrated that lymphopenia induced by dose-intensified temozolomide, provided with antigen-specific vaccination, resulted in superior immune responses. “The dose-intensified temozolomide induces a strong state of lymphopenia,” noted the researchers. “With that comes an opportune moment to introduce an antigen-specific vaccine, which redirects the immune system to put all hands on deck and fight that target.”
The researchers also noted that they found an excellent response rate despite a high proportion of regulatory T cells, which dampen the immune response and rebounded sharply following temozolomide administration. This finding may be cause for optimism, according to the researchers. “If we could preclude this regulatory T-cell rebound, it could have additionally enhancing effects on the pp65 vaccine response.”
The study has some limitations. It was a single-arm study without a control group and a small cohort. “What remains to be determined is whether this combinatorial regimen is strictly dependent on antigen specificity, a question that is best suited for future randomization studies,” they noted.
In addition, the researchers seek to understand the mechanisms that underlie the strong response rate and how to refine this combination therapy to produce even better results. “We want to understand why some patients do better than others,” they concluded.