Adoptive T cell therapy using antigen-specific CD8+ T cells for the treatment of patients with metastatic melanoma: a phase I clinical study
© Author(s); licensee BioMed Central Ltd. 2004
Received: 28 April 2004
Published: 1 July 2004
The adoptive transfer of in vitro induced and expanded tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherpy of cancer. We have previously shown that Melan-A-specific CTL can be generated from HLA-A2.1+ melanoma patients by 4 rounds of in vitro stimulation of purified CD8+ T cells with autologous dendritic cells pulsed with a mutated HLA-A2 binding Melan-A (ELAGIGILTV) peptide. Based on these results we have initiated a pilot study of adoptive T cell therapy in advanced melanoma patients demonstrating that in vitro generated Melan-A specific CTL survive intact in vivo for several weeks and localize preferentially to tumor (Meidenbauer et al., J Immunol 2003, 170: 2161, 2003). Here we report on the clinical results of a phase I study of 12 HLA-A2+ melanoma patients that received at least three i.v. infusions of Melan-A-specific CTL i.v. at 2-week intervals. Each T cell infusion was accompanied by a 6-day course of s.c. IL-2 (3 × 106 IU daily). A total of 51 T-cell infusions were administered, averaging 1.48 × 108 Melan-A multimer+ T cells per infusion, with a range from 0.11–6.58 × 108 Melan-A-specific T cells per infusion. Clinical side effects were mild and consisted of chills and low-grade fever (WHO grade I-II) in 8 out of 12 patients that typically occurred within 6 to 8 h post infusion. Hematological effects, observed after T cell transfer, consisted of an increase in eosinophils up to 30% in 7 out of 12 patients, peaking 24 h post transfer. Clinical and immunological responses consisted of antitumor responses in 3 out of 12 patients (2 PR, 1 mixed response), an elevated frequency of circulating Melan-A multimer+ T cells up to 2% of total CD8+ T cells up to 14 days post transfer, suggesting long-term survival and/or proliferation of transferred CTL, and a complete loss of Melan-A expression in lymph node metastases of 2 patients after T cell transfer. Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients is capable of inducing clinical and systemic tumor-specific immune responses without provoking major side effects.