Phase I trial of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly-diagnosed glioblastoma multiforme (GBM).

ackground: The inherent biologic specificity of immunotherapy offers the prospect of targeting neoplastic cells more precisely. Dendritic cells (DCs) are endowed with an extraordinary ability to activate CD4+ and CD8+ T-cells, and DCs loaded with antigens derived from tumor cells (CMV pp65-LAMP mRNA) have the potential to induce potent antitumor immunity. Furthermore, regulatory T-cells (TRegs ) which induce a state of reversible immunosuppression in mg can be functionally inactivated with anti-CD25 antibody (Ab), while dramatically enhancing vaccine-induced immune responses. Previously a group of 7 pts received DC CMV vaccine with one dose of anti-CD25 Ab (daclizumab). A median overall survival (OS) of 30.3 months (95% CI: 11.8%, 60.8%) was seen without adverse events associated with the vaccine or anti-CD25 Ab therapy. Methods: Eligible were gross totally resected pts with newly diagnosed GBM. Patients underwent leukapheresis followed by standard of care radiation/temozolomide (XRT/TMZ) therapy. After completion of XRT/TMZ, up to 12 cycles of TMZ was administered. On Day 21 of the 1st cycle of post-XRT TMZ Vaccine # 1 was administered. Vaccines #2-3 were given biweekly following vaccine #1. Anti-CD25 Ab (basiliximab) was given twice, one week before vaccines 1 and 2. In this dose escalation study two dose levels were examined: 20 or 40 mg. An additional vaccine was given with each cycle of TMZ to a total of 8. Multiple time-point immune-monitoring by kinetics of number of TRegs and pp65 specific T cells by INFγ ELISPOT was performed for each pt. Results: None of the 28 patients who received any protocol treatment experienced a DLT. One patient experienced an SAE: grade 2 fever and grade 3 confusion. To date, only 2 patients have expired. Among patients who received at least 3 vaccinations, median follow-up is 5.6 months (95% CI: 3.6, 9.9). Median PFS is 7.7 months (95% CI: 3.4, 13.8). Preliminary evaluation of 6 patients' blood provided no evidence of a difference between dose groups in CD4% or Treg% post-basiliximab treatment. Conclusions: Phase I study is closed for accrual; 20 mg of basiliximab is used in Phase II trial. Clinical trial information: NCT00626483.

Duke Scholars

Author Katherine Barnett Peters Neurosurgery, Neuro-Oncology

Author James Emmett Herndon II Biostatistics & Bioinformatics, Division of Biostatistics

Author Henry Seth Friedman Neurosurgery, Neuro-Oncology

Author Darell Doty Bigner Neurosurgery

Author John Howard Sampson Neurosurgery