Dendritic cell vaccination in combination with the TLR7/8 agonist, imiquimod, following radiotherapy and concomitant chemotherapy for newly diagnosed glioblastoma

LB-346

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. Each patient initially received 3 immunizations at 2-week intervals, following completion of surgery and a 6-week course of radio-chemotherapy. Four patients received 1 million DC, 4 received 5 million, and 5 received 10 million DC per immunization. Patients without tumor progression subsequently received booster vaccinations combined with topical administration of the TLR-7/8 agonist imiquimod (^®Aldara). Immunologic responses to tumor antigens were monitored by tetramer staining, CTL assays, and quantitation of regulatory T cell (Treg) frequencies. Clinical tumor growth was monitored by brain MRI scans every 2 months, and the primary clinical endpoint was 2-year survival.

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 known glioma-associated antigens, (e.g., gp100, TRP-2, her-2, survivin, and CMV antigens), were detected in 5 of 7 HLA-A201⁺ patients studies thus far. Preliminary studies suggest that Treg frequencies fluctuate with tumor progression, DC vaccination and myeloablative chemotherapy regimens. To date, 7 of the 13 patients have progressed with a mean overall survival time of 20 months after initial surgical diagnosis. The 6 patients that have not progressed have a mean follow-up time of 34.4 months (range: 13.6 - 50.7 months). Four of these patients have been followed for more than two years without MRI or clinical evidence of tumor progression, and 3 of these patients have follow-up times of more than 3 years since diagnosis. The median PFS to date is 13.6 mos. and median OS is 23 mos. This compares favorably with controls from 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. The adjunctive use of the TLR-7 agonist imiquimod with DC vaccination appears to be non-toxic, and deserves further study. Our results suggest that this active immunotherapy strategy can impact antigen-specific immunologic responses in brain tumor patients following standard radio-chemotherapy.