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

• Published in: Journal of clinical oncology Vol. 27; no. 6; pp. 945 - 952
• Main Authors: Mercedes N. López, Cristian Pereda, Gabriela Segal, Leonel Muñoz, Raquel Aguilera, Fermín E. González, Alejandro Escobar, Alexandra Ginesta, Diego Reyes, Rodrigo González, Ariadna Mendoza-Naranjo, Milton Larrondo, Alvaro Compán, Carlos Ferrada, Flavio Salazar-Onfray
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20-02-2009
• Subjects: Adult; Antineoplastic agents; Biological and medical sciences; Cancer Vaccines - immunology; Dendritic Cells - immunology; Disease Progression; Female; Follow-Up Studies; Humans; Hypersensitivity, Delayed - immunology; Immunotherapy; Male; Medical sciences; Melanoma - immunology; Melanoma - mortality; Melanoma - therapy; Middle Aged; Pharmacology. Drug treatments; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - therapy; Survival Analysis; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - biosynthesis; Tumors; Antineoplastic agent; Human; Pulsed dendritic cell; Allergy; Immunopathology; Skin disease; Prognosis; Transforming growth factor β; Cytokine; Delayed hypersensitivity; Vaccine; Malignant tumor; Survival; Cancerology; Treatment; Antigen presenting cell; Immunotherapy; T-Lymphocyte; Malignant melanoma; Cancer; Prolonged
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.18.0794

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.
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.
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) beta+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001).
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+TGFbeta+ regulatory T cells and in vivo antimelanoma immune response associated to improved patient survival and disease stability.