Replies to post #62129 on NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

128. IMMUNOTHERAPY OF MALIGNANT BRAIN TUMOR USING DENDRITIC CELLS

Takimitsu FUJIMAKI, Takuya OSADA, Wakae FUJIMAKI, Akio ASAI, Youichi SHIBATA, Takehiko UCHIYAMA, and Takaaki KIRINO, Department of Neurosurgery, The University of Tokyo, Department of Transfusion Medicine, The University of Tokyo, Department of Microbiology and Immunology, Tokyo Women's Medical University

Dendritic cells (DCs) are considered the most effective antigen- presenting cells for primary immune responses. In this pilot study, we investigated the ability of autologous dendritic cells which were cultivated ex vivo and were infused to simulate host antitumor immunity. Four patients with recurrent malignant brain tumor [malignant germ cell tumor (mGCT) 1, glioblastoma (GBM) 3] received a serial infusion of DCs under approval of ethical commit- tee of the University of Tokyo. Mononuclear cells were isolated from peripheral blood. DC rich population were infused intravenously 24 h later the isolation. Other mononuclear cells were co-cultured with IL-4 and GM-CSF to expand monocyte derived dendritic cells (MoDCs). In patients whose frozen tumor tissue was available, the DCs were stimulated with tumor lysate. MoDCs were infused once a week for 3 times. The tumor size decreased remarkably in one patient with mGCT and determined to have partial response. In another patient with GBM the tumor showed minor response and other 2 showed no change. Overall response rate was 25%. Immuno- logical parameters of peripheral blood and tumor cyst fluid of a patient with GBM were monitored. There was significant increase in NK cell population (CD56 positive) in the peripheral blood from 11% to 25%. It is considered that this novel immunotherapy could be another tool to enhance antitumor activity of patients with malig- nant brain tumors. The way to enhance immunological responses and adequate monitoring of immunological functions to identify patients who is suitable for this therapy are future consideration,

[flipper44]

The following tertiary endpoints can provide evidence to support the primary
endpoint....

....ENDPOINT: Immunostimulatory response (yes or no). A patient will be
considered a responder if one of the following conditions holds at least one time
point in the study: a) T cell proliferative response to DCVax-L shows a stimulation
index of 2 or greater, b) a greater than 3-fold increase in CD8+ cells staining with
tumor antigen tetramers. -- RK citing old DCVax-L Phase III protocol

Vaccination with tumor lysate-pulsed dendritic cells was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quanti- tative PCR-based assay. Five of ten patients demonstrated robust systemic cytotoxicity as demonstrated by IFN- release by PBMC in response to tumor lysate after vaccination. Using HLA restricted tetramer staining, we identified a significant expansion in CD8+ antigen-specific T-cell clones following DC vaccination in 4 patients, all of whom also demonstrated strong post- treatment antitumor cytotoxicity, as determined by qPCR measurement of IFN message in restimulated PBMC. -- 2004, (Yu, Wheeler) Study IM-20. VACCINATION OF PATIENTS WITH MALIGNANT GLIOMA WITH TUMOR LYSATE-PULSED DENDRITIC CELLS ELICITS ANTIGEN-SPECIFIC CYTOTOXICITY

[Doc logic]

Rkmatters,

I believe the B-cell activation of T-cells and or trafficking of antigens to the lymph zone for DC/T-cell interaction mentioned in your post may be something NWBO eventually talks about as well. Best wishes.