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


METHODS
Patients received a first intravenous injection of 1 x 10(8) 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 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-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.
Di Nicola
Massimo
M
Cristina Gandini Bone Marrow Transplantation Unit, Istituto Nazionale Tumori, Milan, Italy. dinicola@istitutotumori@mi.it
Carlo-Stella
Carmelo
C
Mortarini
Roberta
R
Baldassari
Paola
P
Guidetti
Anna
A
Gallino
Gian Francesco
GF
Del Vecchio
Michele
M
Ravagnani
Fernando
F
Magni
Michele
M
Chaplin
Paul
P
Cascinelli
Natale
N
Parmiani
Giorgio
G
Gianni
Alessandro M
AM
Anichini
Andrea
A
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000097:blood*; D002472:Cell Transformation, Viral; D003713:Dendritic Cells / Q000637:transplantation*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000276:immunology*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*
D018952:Antigens, CD34; D014442:Monophenol Monooxygenase