TY - JOUR
T1 - Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34+-derived dendritic cell vaccination
T2 - A phase I trial in metastatic melanoma
AU - Di Nicola, Massimo
AU - Carlo-Stella, Carmelo
AU - Mortarini, Roberta
AU - Baldassari, Paola
AU - Guidetti, Anna
AU - Gallino, Gian Francesco
AU - Del Vecchio, Michele
AU - Ravagnani, Fernando
AU - Magni, Michele
AU - Chaplin, Paul
AU - Cascinelli, Natale
AU - Parmiani, Giorgio
AU - Gianni, Alessandro M.
AU - Anichini, Andrea
PY - 2004/8/15
Y1 - 2004/8/15
N2 - Purpose: Six American Joint Committee on Cancer stage IV melanoma patients were enrolled into a Phase I study of vaccination with autologous CD34 +-derived dendritic cells transduced with a modified vaccinia Ankara virus encoding human tyrosinase gene (MVA-hTyr). Experimental Design: Patients received a first intravenous injection of 1 × 108 MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval. Results: Treatment was well tolerated, except for low-grade fever (three of six patients), mild erythema at injection site (five of six), and vitiligo (two of six). A partial response, involving shrinkage of an s.c. nodule, later surgically removed, was observed in 1 patient, who then remained disease-free (>850 days). By human lymphocyte antigen tetramer analysis, significant and often long-lasting increases in frequency of T cells directed to tyrosinase368-376 but not to gp100209-217 were documented in periphery of 4 of 5 HLA-A*0201+ patients, a few days after vaccine administration. In addition, maturation phenotype of tyrosinase-specific T cell shifted toward the T effector memory/T terminally differentiate stages (CCR7-CD45RA-/+) in synchrony with the T-cell frequency peaks. By enzyme-linked immunospot in peripheral blood of five HLA-A*0201+ patients, we found that the vaccine could induce interferon γ-releasing effector cells directed to HLA-A*0201/ tyrosinase368-376 and to vaccinia virus HLA-A*0201/H3L 184-192 epitopes. Moreover, an interferon γ response after vaccination was elicited even against the HLA-DRB1-1501/tyrosinase 386-406 epitope in one out of two HLA-A*DRB1-01501+ patients. Conclusions: These results indicate that vaccination with MVA-hTyr-transduced dendritic cells is well tolerated, can possibly produce clinical responses, and activates tyrosinase- and vaccinia virus-specific T cells in vivo. These data suggest a broad utility of the MVA vector for targeting tumor-associated antigens to dendritic cells for tumor immunotherapy.
AB - Purpose: Six American Joint Committee on Cancer stage IV melanoma patients were enrolled into a Phase I study of vaccination with autologous CD34 +-derived dendritic cells transduced with a modified vaccinia Ankara virus encoding human tyrosinase gene (MVA-hTyr). Experimental Design: Patients received a first intravenous injection of 1 × 108 MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval. Results: Treatment was well tolerated, except for low-grade fever (three of six patients), mild erythema at injection site (five of six), and vitiligo (two of six). A partial response, involving shrinkage of an s.c. nodule, later surgically removed, was observed in 1 patient, who then remained disease-free (>850 days). By human lymphocyte antigen tetramer analysis, significant and often long-lasting increases in frequency of T cells directed to tyrosinase368-376 but not to gp100209-217 were documented in periphery of 4 of 5 HLA-A*0201+ patients, a few days after vaccine administration. In addition, maturation phenotype of tyrosinase-specific T cell shifted toward the T effector memory/T terminally differentiate stages (CCR7-CD45RA-/+) in synchrony with the T-cell frequency peaks. By enzyme-linked immunospot in peripheral blood of five HLA-A*0201+ patients, we found that the vaccine could induce interferon γ-releasing effector cells directed to HLA-A*0201/ tyrosinase368-376 and to vaccinia virus HLA-A*0201/H3L 184-192 epitopes. Moreover, an interferon γ response after vaccination was elicited even against the HLA-DRB1-1501/tyrosinase 386-406 epitope in one out of two HLA-A*DRB1-01501+ patients. Conclusions: These results indicate that vaccination with MVA-hTyr-transduced dendritic cells is well tolerated, can possibly produce clinical responses, and activates tyrosinase- and vaccinia virus-specific T cells in vivo. These data suggest a broad utility of the MVA vector for targeting tumor-associated antigens to dendritic cells for tumor immunotherapy.
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U2 - 10.1158/1078-0432.CCR-04-0602
DO - 10.1158/1078-0432.CCR-04-0602
M3 - Article
C2 - 15328176
AN - SCOPUS:4143110212
VL - 10
SP - 5381
EP - 5390
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 16
ER -