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Boosting T Cell-Mediated Immunity to Tyrosinase by Vaccinia Virus-Transduced, CD34⁺-Derived Dendritic Cell Vaccination

A Phase I Trial in Metastatic Melanoma

¹ "Cristina Gandini" Bone Marrow Transplantation Unit, ² Human Tumor Immunobiology Unit, ³ Colo-Rectal Surgery Unit, ⁴ Medical Oncology B Unit, ⁵ Laboratory Medicine Unit, ⁶ Scientific Direction, and ⁷ Human Tumor Immunotherapy Unit, Istituto Nazionale Tumori, Milan, Italy; ⁸ Chair of Medical Oncology, University of Milan, Milan, Italy; and ⁹ Bavarian Nordic GmbH, Martinsried, Germany

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 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 -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 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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