Autologous tumor-lysate pulsed dendritic cell vaccination, together with the TLR-7 agonist 5% imiquimod, and serum pro- inflammatory cytokine levels in glioblastoma patients

Abstract

11021 Background: Standard therapy for glioblastoma, which includes surgery followed by radiation and concurrent chemotherapy, creates a low tumor burden environment that could be ideal for immunotherapeutic approaches. We conducted a Phase I study to assess the safety and immunologic responses of tumor lysate-pulsed dendritic cell (DC) therapy plus topical imiquimod, in combination with standard radio-chemotherapy. Methods: Thirteen patients with newly diagnosed glioblastoma were immunized using autologous tumor lysate-pulsed DC at 2-week intervals, following completion of radio-chemotherapy. The primary clinical endpoint was 2-year survival. Patients without tumor progression subsequently received booster vaccinations combined with topical administration of the TLR-7 agonist, imiquimod. Immunologic responses to tumor antigens were monitored by tetramer staining and intracellular cytokine staining. Measurement of serum cytokine levels (TH1/TH2: IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10) was performed using cytometric bead arrays (CBA). Global gene expression profiling was also performed on pre-treatment tumor samples. Results: All immunizations were well tolerated, with only mild side effects attributable to the DC vaccination and imiquimod adjuvant. Increased levels of CD8+ T cells reactive against tumor antigens, (e.g., gp100, TRP-2, her-2, survivin, and CMV antigens), were detected in 5 patients. CBA measurement of serum cytokine levels revealed small, but detectable levels of TNF-α following the initial DC vaccination. Robust increases in serum TNF-α and IL-6 were observed after booster vaccinations, temporally correlating with imiquimod administration. Clinically, 8 of the 13 patients have progressed, and 6 of those have died. The median PFS to date is 13.9 mos. and median OS is 33.8 mos. This compares favorably to the published literature, with a median PFS of 6.9 mos and OS of 14.6 mos. Conclusions: This study demonstrates the safety and clinical/immunologic effects of an autologous tumor lysate-pulsed DC vaccine for patients with newly diagnosed glioblastoma. Serum TNFα responses may portend therapeutic anti-tumor immune responses to DC vaccination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Northwest Biotherapeutics, Inc. Northwest Biotherapeutics, Inc. Northwest Biotherapeutics, Inc.