2004
IM-20. VACCINATION OF PATIENTS WITH MALIGNANT GLIOMA WITH TUMOR LYSATE-PULSED DENDRITIC CELLS ELICITS ANTIGEN-SPECIFIC CYTOTOXICITY
John S. Yu, Christopher J. Wheeler, Gentao Liu, Han Ying, William H. Yong, Asha Das, and Keith L. Black; Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
The primary goal of this phase I study was to assess the safety and bioac- tivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Parameters meas- ured were adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens. Nine patients with recurrent glioblastoma multiforme and three patients with recurrent anaplastic astrocytoma were treated. One patient with newly diagnosed glioblastoma and one patient with newly diagnosed anaplastic astrocytoma were also included. Patients were vaccinated three times, two weeks apart, with autologous DCs isolated through leukapheresis and pulsed with peptides derived from tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. 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 identi- fied 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. Six patients underwent reoperation for recurrent tumor. A significant CD8+ T cell infiltrate was noted intratumorally in three of six patients. Patients with recurrent glioblastoma were included in a survival analysis and compared to patients who underwent craniotomy for recurrent glioblastoma at our institution during the same time period. The median survival for the study (n = 8) and control (n = 26) groups was 133 and 30 weeks, respectively (P = 0.0013, log rank). This phase I study demonstrated the feasibility, safety, and bioactivity of an autologous tumor lysate- pulsed dendritic cell vaccine for patients with malignant glioma. We demonstrate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.
