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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Division of Neurosurgery, Departments of Surgery, 2 Medicine, 3 Pathology and Laboratory Medicine, and 4 Neurology, 5 The Brain Research Institute, and 6 The Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California at Los Angeles, University of California Los Angeles, Los Angeles, California
Requests for reprints: Linda M. Liau, University of California at Los Angeles Division of Neurosurgery, David Geffen School of Medicine at University of California at Los Angeles, Center for Health Sciences, Room 74-145 CHS, 10833 Le Conte Avenue, Box 956901, Los Angeles, CA 90095-6901. Phone: 310-794-5664; Fax: 310-825-7245; E-mail: lliau{at}mednet.ucla.edu.
Purpose: We previously reported that autologous dendritic cells pulsed with acid-eluted tumor peptides can stimulate T cell–mediated antitumor immune responses against brain tumors in animal models. As a next step in vaccine development, a phase I clinical trial was established to evaluate this strategy for its feasibility, safety, and induction of systemic and intracranial T-cell responses in patients with glioblastoma multiforme.
Experimental Design: Twelve patients were enrolled into a multicohort dose-escalation study and treated with 1, 5, or 10 million autologous dendritic cells pulsed with constant amounts (100 µg per injection) of acid-eluted autologous tumor peptides. All patients had histologically proven glioblastoma multiforme. Three biweekly intradermal vaccinations were given; and patients were monitored for adverse events, survival, and immune responses. The follow-up period for this trial was almost 5 years.
Results: Dendritic cell vaccinations were not associated with any evidence of dose-limiting toxicity or serious adverse effects. One patient had an objective clinical response documented by magnetic resonance imaging. Six patients developed measurable systemic antitumor CTL responses. However, the induction of systemic effector cells did not necessarily translate into objective clinical responses or increased survival, particularly for patients with actively progressing tumors and/or those with tumors expressing high levels of transforming growth factor ß2 (TGF-ß2). Increased intratumoral infiltration by cytotoxic T cells was detected in four of eight patients who underwent reoperation after vaccination. The magnitude of the T-cell infiltration was inversely correlated with TGF-ß2 expression within the tumors and positively correlated with clinical survival (P = 0.047).
Conclusions: Together, our results suggest that the absence of bulky, actively progressing tumor, coupled with low TGF-ß2 expression, may identify a subgroup of glioma patients to target as potential responders in future clinical investigations of dendritic cell–based vaccines.
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