Boosting T Cell-Mediated Immunity to Tyrosinase by Vaccinia Virus-Transduced, CD34 super(+)-Derived Dendritic Cell Vaccination: A Phase I Trial in Metastatic Melanoma

PURPOSE: Six American Joint Committee on Cancer stage IV melanoma patients were enrolled into a Phase I study of vaccination with autologous CD34 super(+)- 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 10 super(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 sub(368-376) but not to gp100 sub(209-217) were documented in periphery of 4 of 5 HLA-A*0201 super(+) 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 super(-)CD45RA super(-/+)) in synchrony with the T-cell frequency peaks. By enzyme-linked immunospot in peripheral blood of five HLA-A*0201 super(+) patients, we found that the vaccine could induce interferon gamma -releasing effector cells directed to HLA- A*0201/tyrosinase sub(368-376) and to vaccinia virus HLA-A*0201/H3L sub(184-192) epitopes. Moreover, an interferon gamma response after vaccination was elicited even against the HLA-DRB1-1501/tyrosinase sub(386-406) epitope in one out of two HLA-A* DRB1-01501 super(+) 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.