Originally published as JCO Early Release 10.1200/JCO.2005.01.6816 on October 31 2005

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Immunogenicity, Including Vitiligo, and Feasibility of Vaccination With Autologous GM-CSF–Transduced Tumor Cells in Metastatic Melanoma Patients

Rosalie M. Luiten, Esther W.M. Kueter, Wolter Mooi, Maarten P.W. Gallee, Elaine M. Rankin, Winald R. Gerritsen, Shirley M. Clift, Willem J. Nooijen, Pauline Weder, Willeke F. van de Kasteele, Johan Sein, Paul C.M. van den Berk, Omgo E. Nieweg, Anton M. Berns, Hergen Spits, Gijsbert C. de Gast

From the Departments of Medical Oncology, Immunology, Pathology, Clinical Chemistry, Surgical Oncology, and Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands; and Cell Genesys, Foster City, CA

Address reprint requests to G.C. de Gast, MD, PhD, Professor of Clinical Immunotherapy, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: g.d.gast{at}nki.nl.

PURPOSE: To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients.

PATIENTS AND METHODS: Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays.

RESULTS: The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1– or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1– and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon- on specific antigenic stimulation.

CONCLUSION: We conclude that vaccination with GM-CSF–transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.

Supported by Cell Genesys, Foster City, CA. R.M.L. and E.W.M.K. were supported by Dutch Cancer Society Grant No. NKI99-2048.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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