Study of DC Vaccination Against Glioblastoma

Despite the advances in diagnosis and treatment (surgery +radiation +chemotherapy), median survival for patients with newly diagnosed brain glioblastoma multiform (GBM) is about one year, for recurrent GBM is about 4 months. Recently, immunotherapy has emerged as a novel treatment strategy for glioma with improving patient survival. Usually, processed tumor antigens from the patient's own tumor or a peptide vaccine is capable of producing an anti-glioma response. Our previous experiment revealed that the CD133+ tumor stem-like cells associated antigens could elicit highly intensive immune response against human malignant glioma , and in phase I study, we have confirmed that DC vaccine loaded with glioma stem-like cells associated antigens against malignant glioma in recurrent patients was of safety .

Autologous DCs will be obtained from peripheral blood mononuclear cells (PBMCs) from each patient. Stem-like cells associated antigens (SAA) will be prepared with glioma stem-like cells that are harvested from patients with GBM and primary cultured and sorted flowcytometrically and then irradiated. Approximately 4 weeks will be required for vaccine production and the first vaccine administration. Each patient will receive an injection of DCs at his/her assigned dose once every week during the first 6 week. The dose of DCs is defined as 8~10×10^6.

Clinical trials that utilize DCs for immunotherapy have demonstrated significant survival benefit for patients who exhibit robust immune responses against tumor cells. Unfortunately, at the present time the majority of clinical trials were in phase I that illustrated the safety. The efficacy of DCs against glioblastoma is still lack of sufficient randomized phase II study. According to our previous phase I study, here we designed this clinical trial in a triple-blind randomized manner to validate the efficacy of DCs vaccination.

Recently，an exploratory randomized phase II clinical trial have been completed （Cancer immunology &immunotheapy ，2018，1677，1677-1688 ； PubMed ID: 30159779）， 43 GBM patients were randomized after surgery at a 1:1 ratio to receive either DCV (n = 22) or normal saline placebo (n = 21). Overall survival (OS) and progression-free survival (PFS) were analysed. Participants were stratified into different molecular subgroups based on the mutation (MT) status of isocitrate dehydrogenase (IDH1/2) and telomerase reverse transcriptase (TERT). Plasma cytokine levels, tumor-infiltrating lymphocyte numbers and immune co-inhibitory molecules PD-L1 and B7-H4 were also assessed. Multivariate Cox regression analysis revealed that DCV treatment significantly prolonged OS (p = 0.02) after adjusting for IDH1 and TERT promoter MT and B7-H4 expression, primary vs recurrent GBM. Among IDH1wild type (WT) TERTMT patients, DCV treatment significantly prolonged OS (p < 0.01) and PFS (p = 0.03) and increased plasma levels of cytokines CCL22 and IFN-γ compared with placebo. Patients with low B7-H4 expression showed significantly prolonged OS (p = 0.02) after DCV treatment.

In the present study, IDH1WTTERTMT subgroups of GBM patients more responsive to GSC DCV-based specific active-immunotherapy. However，It is noted that IDH1WTTERTMTGBM patients was analysed in a cohort samples which are not randomlized and the present study population is too small to evaluate conclusively demographic criteria for entry and patient recruitment. the results of the present study should be confirmed in a random cohort of IDH1WTTERTMT GBM patients. Accordingly , we made some modifications to the original plan, and are currently recruiting new participants.