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

• Published in: Journal of clinical oncology Vol. 23; no. 35; pp. 8978 - 8991
• Main Authors: LUITEN, Rosalie M, KUETER, Esther W. M, SEIN, Johan, VAN DEN BERK, Paul C. M, NIEWEG, Omgo E, BERNS, Anton M, SPITS, Hereen, DE GAST, Giisbert C, MOOI, Walter, GALLEE, Maarten P. W, RANKIN, Elaine M, GERRITSEN, Winald R, CLIFT, Shirley M, NOOIJEN, Willem J, WEDER, Pauline, VAN DE KASTEELE, Willeke F
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 10.12.2005; Lippincott Williams & Wilkins
• Subjects: Adjuvants, Immunologic; Adult; Aged; Antigens, Neoplasm - immunology; Autoimmune Diseases - etiology; Biological and medical sciences; Cancer Vaccines - adverse effects; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Cytotoxicity, Immunologic; Dermatology; Drug Administration Schedule; Feasibility Studies; Female; Granulocyte-Macrophage Colony-Stimulating Factor - adverse effects; Granulocyte-Macrophage Colony-Stimulating Factor - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - therapeutic use; Humans; Male; Medical sciences; Melanoma - drug therapy; Melanoma - immunology; Middle Aged; Neoplasm Proteins - immunology; Peptide Fragments - immunology; Pigmentary diseases of the skin; T-Lymphocytes - immunology; Tumors; Vitiligo - etiology; Human; Skin disease; Pigmentation disorder; Immune response; Vaccination; Malignant tumor; Metastasis; Prevention; Vitiligo; Cancerology; Immunogenicity; Malignant melanoma; Advanced stage; Feasibility; Transduction; Tumor cell; Granulocyte macrophage colony stimulating factor
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2005.01.6816

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. 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. 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-gamma on specific antigenic stimulation. 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.