Cmv-Specific Immuno-Dysregulation In Recurrent Glioblastoma Patients Can Be Overcome With Therapeutic Vaccination Which Is Associated With Tumor Response And Overall Survival Benefits In A Phase I/Iia Study

Numerous independent laboratories using several techniques have demonstrated cytomegalovirus (CMV) antigens in over 90% of glioblastoma (GBM) tumors. We initiated a phase I/IIA multicenter study designed to demonstrate safety and determine the most immunogenic dose of an enveloped virus-like particle (eVLP) vaccine expressing the CMV gB and pp65 antigens for treatment of recurrent GBM patients. In Part A of the trial, 6 patients in each of 3 different antigen dose cohorts were vaccinated monthly and followed until tumor progression, with PBMCs collected 2 weeks after each vaccination. Surprisingly, only 7/18 patients enrolled in Part A of the trial had baseline CMV-specific antibody (Ab) titers. This was unexpected given the documented high prevalence of CMV antigens in GBM tumor samples as well as epidemiological data demonstrating much higher CMV Ab seropositive rates in otherwise healthy individuals of a comparable age. In the low dose cohort, 4/6 patients had baseline CMV Ab titers. Of these 4 patients,vaccination boosted strong T cell responses in 2 patients (based on IFN-γ ELISPOT against CMV gB and pp65 antigens). Vaccination did not boost T-cell responses in the CMV Ab-negative patients. In the intermediate dose cohort, among 4 evaluable patients, T cell responses were robustly boosted in the only patient with a baseline CMV Ab titer. In marked contrast, the T-cell responses in the high dose cohort were boosted in 3/5 evaluable patients, all of which were CMV Ab seronegative at baseline. Moreover, the T-cell responses correlated with tumor responses (stable disease based on 2 or more stable MRI scans) as well as improved PFS and 6 month OS relative to vaccine non-responders. To further understand the apparent disconnect between baseline CMV Ab titers and vaccine-mediated impact on tumor and clinical responses, we developed a more sensitive flow cytometry-based assay which evaluated proliferating (Ki-67-positive) gB- and pp65-specific T cells within naive, central memory (CD45RA-CCR7+) or effector memory (CD45RA-CCR7-) subsets. Among 2/3 tested vaccine responders evaluated thus far in the high dose cohort that were CMV Ab negative at baseline, high frequencies of effector memory cells (~2% total CD3+CD4+ T cells) against both the CMV pp65 and gB antigens were detected at baseline. Collectively, these data suggest that CMV-specific immune dysregulation exists in a substantial number of rGBM patients, which can be overcome with the appropriate dose of a CMV vaccine immunotherapeutic. Importantly, vaccine-mediated boosting of CMV immunity correlates with improved tumor response and clinical outcomes and warrants further confirmation. Citation Format: Tamara Berthoud, Felicia Deonarine, Spenser Ng Cheong Chung, Catalina Soare, Francisco Diaz-Mitoma, David E. Anderson. CMV-specific immuno-dysregulation in recurrent glioblastoma patients can be overcome with therapeutic vaccination which is associated with tumor response and overall survival benefits in a Phase I/IIA study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6538.