ATLnsider, Toll-like receptor (TLR) agonists (e.g., imiquimod, poly-ICLC) has been tested in a Phase I/II clinical trial (NCT00068510 , July 2003- October 2007) These immune response modifiers were used only in the booster phase of the protocol, after patients had shown acceptable toxicity profiles to DC-lysate vaccinations alone.
In this phase I study, we report the safety, feasibility, and bioactivity of a vaccine comprised of autologous DC pulsed with autologous tumor lysate as an adjuvant following surgical resection with standard chemoradiotherapy. Unlike our previous reported DC vaccination strategy (8) and those reported by other groups (6, 9–13, 29), we included “booster” vaccinations with the innate immune response modifiers, 5% imiquimod (Aldara), or poly-ICLC (Hiltonol) based on our preclinical studies suggesting that proinflammatory innate immune signals could enhance DC activation, trafficking to lymph nodes, and the priming of antitumor antigen-specific T lymphocytes (15). There were no dose-limiting toxicities and no detectable differences in safety or efficacy among the 3 DC dose levels tested. Of note, there was a significant difference in the average age of patients in the 10 million DC cohort compared with the other dose cohorts, which could influence the difference in OS. However, another possible hypothesis is that this trend in the data was a reflection of a dilutional decrease in antigens available for presentation by DC at the highest DC dose cohort (10 × 106 cells), given that the quantity of lysate was fixed (at 100 µg per dose) despite the increased DC cell dose.
The concomitant administration of 5% imiquimod or poly-ICLC with DC vaccination was also found to be safe and did not result in any additional toxicity or adverse events. To our knowledge, this is the first report of the use of TLR agonists in conjunction with DC vaccination strategies in brain tumor patients. Because TLR agonists were used only in patients in the booster phase, it is unclear whether or to what extent the addition of the TLR agonists contributed to the potential efficacy and OS of these patients. Furthermore, imiquimod and poly-ICLC are two different biological agents, targeting different TLRs. Imiquimod activates TLR-7 whereas poly-ICLC activates TLR-3, but both induce proinflammatory cytokine secretion. These complexities make it somewhat difficult to determine how these innate immune modifiers actually contributed to our study endpoints. Nevertheless, this study establishes the safety of these TLR agonists in conjunction with glioma lysate-loaded DC, and further phase II studies directly comparing these TLR agonists at the time of initial vaccination (not only in the booster phase) are currently underway.
Although the number of glioblastoma patients entered in this phase I clinical trial was not powered to measure efficacy, the clinical results of this trial are still noteworthy. The median OS from the time of initial surgical diagnosis was 31.4 months for all glioblastoma patients (n = 23) treated in this study, including both those enrolled as newly diagnosed and recurrent tumor patients. For those treated in the newly diagnosed setting, the OS was 35.9 months; and the OS was 17.9 months for those who received vaccination at recurrence. In addition, we have had 3 patients surviving more than 6 years to date. Such statistics are compelling in the face of the expected median survival for this disease, which is currently still reported as approximately 14 months for newly diagnosed patients that receive standard surgery, radiation, and temozolomide chemotherapy (4, 30, 31). This compares favorably even when compared with published data for the best clinically defined prognostic group of glioblastoma patients (recursive partitioning analysis; RPA class III: age < 50 years and KPS ≥ 90), whose 2-year survivals were 40% and 29% for RPA III and IV patients, respectively, following treatment with standard radiation and temozolomide (31). Such data are also favorable compared with other recent brain tumor DC-based vaccine trials without booster injections and TLR adjuvants, where the OS was reported as 21.4 months (mean, 11 newly diagnosed and 23 recurrent glioblastoma patients; ref. 10) and 9.6 months (median) in a recurrent glioblastoma population (6).
