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Intranodal Administration of Peptide-Pulsed Mature Dendritic Cell Vaccines Results in Superior CD8⁺ T-Cell Function in Melanoma Patients

Isabelle Bedrosian, Rosemarie Mick, Shuwen Xu, Harvey Nisenbaum, Mark Faries, Paul Zhang, Peter A. Cohen, Gary Koski, Brian J. Czerniecki

From the Harrison Department of Surgical Research and the Departments of Surgery, Biostatistics and Epidemiology, Radiology, and Pathology, University of Pennsylvania, Philadelphia, PA; and the Center for Surgery Research, Cleveland Clinic, Cleveland, OH.

Address reprint requests to Brian J. Czerniecki, MD, PhD, Department of Surgery, University of Pennsylvania, 4 Silverstein, 3400 Spruce St, Philadelphia, PA 19104; e-mail: brian.czerniecki{at}uphs.upenn.edu.

Purpose: We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes.

Patients and Methods: We performed a randomized, phase I, dose-escalation study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses.

Results: Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8⁺ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8⁺ T cells that respond by cytokine secretion to peptide-pulsed targets (six [85.7%] of seven IN patients v two [33%] of six ID patients v none [0%] of six IV patients; P = .005) and de novo DTH (seven [87.5%] of eight IN patients v two [33.3%] of six ID patients v one [14.3%] of seven IV patients; P = .01) compared with other routes.

Conclusion: Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.

Supported by American Cancer Society grant no. RPG 99-0029.

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