Efficacy of therapeutic dendritic cell vaccines (DCV) can be limited by immunosuppressive mechanisms such as regulatory T cells (Treg) overrepesented in the micromilieu of the tumor. Here, we investigated whether a reduction of Treg with metronomic cyclophosphamide (metrCyc) might be a feasible option to improve vaccine efficacy. 7 patients with replased glioblastoma were treated in the pilot phase of the HIT-HGG Rez Immunovac study (5 pediatric, 2 adult patients). After reoperation and monocyte-apheresis, patients received 4 weekly doses of autologous, TNFa/IL-1ß matured DCs pulsed with tumor lysate. Thereafter 4 monthy, and subsequently threemonthly boosts with tumor lysate were given. The intradermal injection site was prepared with topical imiquimod. Additionally, patients were pretreated with oral metrCyc 2-4 weeks before the first vaccination. MetrCyc was well tolerated with one mild and transient leukopenia in a patient, who received a parallel re-irradiation boost. All patients received at least 7 vaccines (4xDCs, 3xlysate boosts). Treg frequency decreased by 32%, but returned to normal levels after cessation of metrCyc. Importantly, 6/6 analyzed patients showed a positive (>1.5fold increase) IFNg-response of varying magnitude and duration towards the autologous tumor lysate in a IFNg-PCR assay. Furthermore, we observed an increase in VLA4+ T-cells induced by the vaccine, both in the CD4 as well as the CD8 compartment. So far, all patients relapsed after a mean of 4.8 months, however, overall survival is currently 15.2 months with 4/7 patients being still alive after a median follow-up of 21 months (range 12-27 months). One patient is disease-free after reoperation and continuation of vaccination for 26 months now. 6-month overall survival was 86%. We conclude that DC vaccination in combination with partial Treg depletion with metrCyc is feasible, safe, and possibly related with a higher than expected frequency of positive IFNg-responses towards tumor tissue. These pilot data warrant verification in the full HIT-HGG Rez Immunovac trial (Eudra-CT 2013-000419-26), which will start to recruit patients soon.

Citation Format: Matthias Eyrich, Jürgen Krauss, Mario Löhr, Antje Technau, Johannes Rachor, Camelia Monoranu, Monika Warmuth-Metz, Matthias Wölfl, Christof Kramm, Paul Gerhardt Schlegel. Dendritic cell vaccination with partial Treg depletion in relapsed glioblastoma – results from the pilot phase of the HIT-HGG Rez Immunvac study. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A045.

©2016 American Association for Cancer Research.
2016