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Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8⁺ T Cells for the Treatment of Patients With Metastatic Melanoma

Andreas Mackensen, Norbert Meidenbauer, Sandra Vogl, Monika Laumer, Jana Berger, Reinhard Andreesen

From the Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany

Address reprint requests to Andreas Mackensen, MD, Department of Hematology/Oncology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93042 Regensburg, Germany; e-mail: andreas.mackensen{at}klinik.uni-regensburg.de

Purpose The adoptive transfer of in vitro generated tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherapy of cancer. A phase I study was conducted to test the feasibility, safety, and survival of adoptively transferred Melan-A–specific CTL lines in melanoma patients.

Patients and Methods Eleven HLA-A2⁺ patients with metastatic melanoma received at least three intravenous infusions of Melan-A–specific CTL at 2-week intervals. CTL were generated by four rounds of in vitro stimulation of purified CD8⁺ peripheral blood lymphocytes with autologous dendritic cells pulsed with an HLA-A2 binding Melan-A peptide. Each T-cell infusion was accompanied by a 6-day course of low-dose interleukin-2.

Results A total of 52 T-cell infusions were administered, averaging 2.1 x 10⁸ Melan-A–specific CTL per infusion. Clinical adverse effects were mild and consisted of chills and low-grade fever in seven of 11 patients. Clinical and immunologic responses revealed an antitumor response in three of 11 patients (one complete regression, one partial regression, one mixed response), an elevated frequency of circulating Melan-A tetramer⁺ T cells up to 2 weeks in all the patients with a maximal frequency of 2% of total CD8⁺ T cells, an increase in eosinophils to up to 50% in seven of 11 patients, and a selective loss of Melan-A expression in lymph node metastases in two evaluated patients after T-cell transfer.

Conclusion Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.

Supported in part by the German José Carreras Leukemia Foundation (DJCLS H99-066) and Deutsche Krebshilfe (70-3069).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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