Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patients with glioblastoma.

BACKGROUND: The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting. METHODS: We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9-18 vaccines containing 10(7) cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456. RESULTS: Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test). CONCLUSION: These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival.

Working memory in recurrent brief depression: an fMRI pilot study.

BACKGROUND: We examined women with recurrent brief depression (RBD) with and without episodes of hypomania with an n-back working memory paradigm to assess how working memory load affects the neurological network corresponding to working memory for these groups. METHOD: Participants (n=33) were medication-free and mostly euthymic while performing a 1-back and a 2-back task in the fMRI scanner. Differential activation results between the tasks were assessed globally and within seven predefined regions of interest associated with working memory activation. The patient groups were compared with healthy women and matched for age, handedness, and length of education. RESULTS: Poor task modulation was observed in both RBD groups in the prefrontal cortex (BA9) in the 1-back task and activation during the 2-back task, particularly in a subgroup with a history of brief hypomanic episodes (RBD-H) compared with the subgroup without such episodes (RBD-O). Task modulation in the right parahippocampal gyrus (BA27) distinguished the RBD-O group, and task modulation in the right insula clearly distinguished the RBD-H group. LIMITATIONS: Small sample size and recruitment of most patients through media that may induce a selection bias towards better-functioning subjects. CONCLUSION: The observed lack of deactivation within the right insula has also been reported in patients with bipolar I disorders. Activation differences in BA9 and the parahippocampal region between RBD patients with and without a history of hypomania suggest different functional hypersensitivity of early limbic regions and ability to sustain attention and working memory, respectively, possibly identifying functional differences between the two subgroups.