Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells.
OBJECTIVE
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.


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) beta+ regulatory T cells compared to DTH-negative patients (1.54% v 5.78%; P < .0001).


CONCLUSIONS
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.
López
Mercedes N
MN
Millennium Nucleus on Immunology and Immunotherapy, Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile.
Pereda
Cristian
C
Segal
Gabriela
G
Muñoz
Leonel
L
Aguilera
Raquel
R
González
Fermín E
FE
Escobar
Alejandro
A
Ginesta
Alexandra
A
Reyes
Diego
D
González
Rodrigo
R
Mendoza-Naranjo
Ariadna
A
Larrondo
Milton
M
Compán
Alvaro
A
Ferrada
Carlos
C
Salazar-Onfray
Flavio
F
D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D008875:Middle Aged; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D019496:Cancer Vaccines; D016212:Transforming Growth Factor beta