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 X 108 MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval. Results: Treatment was well tolerated, except for lowgrade 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 I 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 tyrosinase(368-376) but not to gp100(209-217) 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,gamma-releasing effector cells directed to HLA-A*0201/tyrosinase(368-376) and to vaccinia virus HLA-A*0201/H3L(184-192) epitopes. Moreover, an interferon gamma response after vaccination was elicited even against the HLA-DRBl-1501/tyrosinase(386-406) epitope in one out of two HLA-A* DRBI-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.

Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34+-derived dendritic cell vaccination: a phase I trial in metastatic melanoma / M. Di Nicola, C. Carlo-Stella, R. Mortarini, P. Baldassari, A. Guidetti, F. Gallino, M. Del Vecchio, F. Ravagnani, M. Magni, P. Chaplin, N. Cascinelli, G. Parmiani, A. Gianni, A. Anichini. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 10:16(2004 Aug 15), pp. 5381-5390. [10.1158/1078-0432.CCR-04-0602]

Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34+-derived dendritic cell vaccination: a phase I trial in metastatic melanoma

C. Carlo-Stella;A. Guidetti;A. Gianni;
2004-08-15

Abstract

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 X 108 MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval. Results: Treatment was well tolerated, except for lowgrade 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 I 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 tyrosinase(368-376) but not to gp100(209-217) 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,gamma-releasing effector cells directed to HLA-A*0201/tyrosinase(368-376) and to vaccinia virus HLA-A*0201/H3L(184-192) epitopes. Moreover, an interferon gamma response after vaccination was elicited even against the HLA-DRBl-1501/tyrosinase(386-406) epitope in one out of two HLA-A* DRBI-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.
hematopoietic progenitor cells; american joint committee; antigen-presenting cells; peripheral-blood; ex-vivo; CD34(+) progenitors; langerhans cells; lymphocytes; peptide; generation
Settore MED/06 - Oncologia Medica
CLINICAL CANCER RESEARCH
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/19849
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