Originally published as JCO Early Release 10.1200/JCO.2008.18.0794 on January 12 2009

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Prolonged Survival of Dendritic Cell–Vaccinated Melanoma Patients Correlates With Tumor-Specific Delayed Type IV Hypersensitivity Response and Reduction of Tumor Growth Factor β-Expressing T Cells

From the Millennium Nucleus on Immunology and Immunotherapy, Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile; Research Support Office, Clinical Hospital of the University of Chile, Santiago; and the Regional Hospital of Concepción, Concepción, Chile.

Corresponding author: Flavio Salazar-Onfray, MD, Programa Disciplinario de Inmunología, Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Avenida Independencia 1027, Santiago, Chile; e-mail: fsalazar{at}inmunotron.med.uchile.cl.

Purpose The aim of this work was to assess immunologic response, disease progression, and post-treatment survival of melanoma patients vaccinated with autologous dendritic cells (DCs) pulsed with a novel allogeneic cell lysate (TRIMEL) derived from three melanoma cell lines.

Patients and Methods Forty-three stage IV and seven stage III patients were vaccinated four times with TRIMEL/DC vaccine. Specific delayed type IV hypersensitivity (DTH) reaction, ex vivo cytokine production, and regulatory T-cell populations were determined. Overall survival and disease progression rates were analyzed using Kaplan-Meier curves and compared with historical records.

Results The overall survival for stage IV patients was 15 months. More than 60% of patients showed DTH-positive reaction against the TRIMEL. Stage IV/DTH-positive patients displayed a median survival of 33 months compared with 11 months observed for DTH-negative patients (P = .0014). All stage III treated patients were DTH positive and remained alive and tumor free for a median follow-up period of 48 months (range, 33 to 64 months). DTH-positive patients showed a marked reduction in the proportion of CD4+ transforming growth factor (TGF) β+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001).

Conclusion Our findings strongly suggest that TRIMEL-pulsed DCs provide a standardized and widely applicable source of melanoma antigens, very effective in evoking antimelanoma immune response. To our knowledge, this is the first report describing a correlation between vaccine-induced reduction of CD4+TGFβ+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.

Supported by grants from the Fund for the Promotion of Scientific and Technological Development (FONDEF DO2I1088), the National Fund for Scientific and Technological Development (FONDECYT 1060935 and 1070559), Millennium Nucleus on Immunology and Immunotherapy P04/030-F.

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

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