A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fluorescence-guided surgery in newly diagnosed glioblastoma patients

Abstract

Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival.

Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were finally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan-Meier method. Immune response were assessed in blood samples obtained before each vaccines.

Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufficient resection. Median age was 61 years (range 42-70). Karnofsky performance score (KPS) was 90-100 in 29%, 80 in 35.5% and 60-70 in 35.5% of cases. MGMT (O6-methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse effects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7-16) and median OS was 23.4 months (95% CI 16-33.1). Increase in post-vaccination tumor specific immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correlation between immune response and survival was found.

Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and ClinicalTrials.gov Identifier: NCT01006044 retrospectively registered.

Keywords: Dendritic cell; Glioblastoma; Immunotherapy; Overall survival.

Figures

Fig. 1

Treatment schedule. All patients were scheduled to receive conventional radio-chemotherapy with up to 12 cycles of adjuvant temozolomide or until disease progression. The first intradermal DCs administrations were scheduled prior to radiotherapy, and the second 3 weeks after radiotherapy. This was followed by two monthly, four bi-monthly, and subsequent quarterly administrations until the end of all available doses. During adjuvant TMZ treatment, DC were administered on day 21 of the corresponding cycle. Vaccines were administered intradermally

Fig. 2

PFS and OS from patients treated with standard treatment plus dendritic cells vaccines. The patients were treated with standard treatment: radio-chemotherapy followed by chemotherapy of maintenance plus DC vaccines. PFS and OS were analysed with Kaplan–Meier method: a PFS in months from patients vaccinated; b OS in months from all patients, c OS in months from patients with MGMT unmethylated vs methylated

Fig. 3

Tumor specific immune response in vaccinated patients. Blood samples were obtained before each vaccine. Mononuclear cells (PBMCs) before each vaccine were cryopreserved and thawed together to evaluate changes in proliferation of PBMC stimulated in presence of antigen (a) and number of IFN-γ producing cells by IFNγ enzyme-linked immunospot or ELISPOT after in vitro stimulation with pulsed DC (b)