Limited Antitumor T Cell Response in Melanoma Patients Vaccinated with Interleukin-2 Gene-Transduced Allogeneic Melanoma Cells

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Abstract
We have immunized advanced melanoma patients with a HLA-A2-compatible human melanoma line genetically modified to release interleukin-2 (IL-2), to elicit or increase a T cell-mediated anti-melanoma response that may affect distant lesions. Twelve stage-IV patients were injected subcutaneously at days 1, 13, 26, and 55 with IL-2 gene-transduced and irradiated melanoma cells at doses of 5 or 15 × 107 cells. Both local and systemic toxicities were mild, consisting of transient erythema at the vaccination site; fever occurred in a minority of patients. Three mixed responses were recorded. Seven patients were evaluable for immunological studies. Mixed tumor–lymphocyte cultures carried out with different allogeneic HLA-A2-matched melanoma lines as stimulators and targets revealed an increase in the MHC-unrestricted, but no changes in the MHC-restricted, cytotoxicity in peripheral blood lymphocytes (PBL) obtained after vaccination as compared with those obtained before vaccination. Increased recognition of the tyrosinase 368–376 peptide occurred in post-vaccination PBL of one patient, whereas a weak increase in recognition of the gp100 280–288 peptide was detectable in another patient; these 2 patients also recognized the gp100 457–466 peptide. After in vitro, stimulation with the only available autologous melanoma line, CD4+ cells with autologous tumor-specific cytotoxicity and ability to release interferon-γ (IFN-γ) were found in post- but not in pre-vaccination PBL. In the same patient, as well as in another patient, limiting dilution analysis showed that vaccination resulted in an increased frequency of melanoma-specific cytotoxic T lymphocyte (CTL) precursors. These results indicate that vaccination with cells releasing IL-2 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although this response occurred in a minority of the melanoma patients studied. Advanced melanoma patients were immunized with a HLA-A2-compatible melanoma line genetically modified to release interleukin-2 (IL-2) to elicit or increase an anti-melanoma T cell response. Patients were injected subcutaneously at days 1, 13, 26, and 55 with 5 or 15 × 107 irradiated cells. Toxicity was mild and only mixed clinical responses were recorded. A significant increase in MHC-unrestricted but not MHC-restricted cytotoxicity against different targets was observed in post-vaccination PBL after 4 weeks of mixed tumor–lymphocyte culture. Specific reactivity of CTL directed against tyrosinase and gp100 melanoma antigens was found to be increased in post-vaccination PBL of 2 out of 5 patients. When an autologous melanoma line could be used as in vitro stimulator, CTL able to release interferon-γ (IFN-γ) and specifically lyse the autologous melanoma were found in post-vaccination PBL. In the same case, limiting dilution analysis revealed a significant increased frequency of anti-melanoma CTL after vaccination. These results indicate that IL-2 gene-transduced melanoma cells can augment a T cell-specific immune response in a fraction of immunized patients.

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