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Adoptive Transfer of Tumor-Reactive Melan-A-Specific CTL Clones in Melanoma Patients Is Followed by Increased Frequencies of Additional Melan-A-Specific T Cells¹

Virginie Vignard^2,*, Brigitte Lemercier^2,, Annick Lim, Marie-Christine Pandolfino^*,, Yannick Guilloux^*,, Amir Khammari^*,¶, Catherine Rabu^*, Klara Echasserieau^*,||, François Lang^*,||, Marie-Lise Gougeon^3,, Brigitte Dreno^*,,¶, Francine Jotereau^3,*, and Nathalie Labarriere^3,*

^* Unit Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 601, Nantes, France; Faculté des Sciences de Nantes, Nantes, France; Antiviral Immunity, Biotherapy and Vaccine Unit, INSERM Unité 668, Institut Pasteur, Paris, France; Unit of Cellular and Gene Therapy, Centre Hospitalier Régional Universitaire de Nantes, Nantes, France; ^¶ Unit of Skin Cancer, Centre Hospitalier Régional Hotel Dieu, Nantes, France; and ^|| Recombinant Protein Facility, Institut Féderatif de Recherche 26, Nantes, France

In this study, we report the adoptive transfer of highly tumor-reactive Melan-A-specific T cell clones to patients with metastatic melanoma, and the follow-up of these injected cells. These clones were generated from HLA-A*0201 patients by in vitro stimulations of total PBMC with the HLA-A*0201-binding Melan-A peptide analog ELAGIGILTV. Ten stage IV melanoma patients were treated by infusion of these CTL clones with IL-2 and IFN-. The generated T cell clones, of effector/memory phenotype were selected on the basis of their ability to produce IL-2 in response to HLA-A*0201 Melan-A-positive melanoma lines. Infused clones were detected, by quantitative PCR, in the blood of three patients for periods ranging from 7 to 60 days. Six patients showed regression of individual metastases or disease stabilization, and one patient experienced a complete response, but no correlation was found between the detection of the infused clones in PBMC or tumor samples and clinical responses. Nonetheless, frequencies of Melan-A/A2-specific lymphocytes, measured by tetramer labeling, increased after treatment in most patients. In one of these patients, who showed a complete response, this increase corresponded to the expansion of new clonotypes of higher avidity than those detected before treatment. Together, our results suggest that infused CTL clones may have initiated an antitumor response that may have resulted in the expansion of a Melan-A-specific CTL repertoire.

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