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High Avidity Melanoma-reactive Cytotoxic T Lymphocytes Are Efficiently Induced from Peripheral Blood Lymphocytes on Stimulation by Peptide-pulsed Melanoma Cells¹

Institut de Biologie, INSERM U463, 44093 Nantes Cédex 1 [N. G., N. L., S. L., J-F. F., Y. G., E. D., F. J.]; Unité de thérapie cellulaire et génique, CHRU de Nantes, 44093 Nantes [M-C. P.]; and Departement de dermatologie du CHRU de Nantes, 44093 Nantes [B. D.], France

To design an efficient procedure to expand high avidity melanoma reactive T cells and to perform immunotherapies, we compared conditions of peripheral blood lymphocyte (PBL) stimulation by Melan-A/MART-1 peptides. Avidity of induced CTLs was evaluated by measuring their lysis and cytokine secretion to peptide-pulsed transporter-associated protein-deficient cells and to melanoma cells. In side-by-side experiments, we show that melanoma cells, either allogeneic or autologous, induced the growth of high avidity Melan-A-reactive CTLs from all donors, whereas essentially low avidity T cells were induced by peptide-pulsed PBLs. We also show that at least two cytokines, interleukin-6 and interleukin-2, were required to promote the growth of high avidity CTLs. Once sorted by tetramer labeling or cloning, the specificity and reactivity to tumor cells of peptide-specific T cells induced by allogeneic melanoma cells were confirmed.

We then describe a relatively simple and efficient procedure that allowed us to obtain systematically high amounts (in the range of billion) of high avidity Melan-A/MART-1-specific T cells from the PBLs of HLA-A2 melanoma patients and healthy donors in 3 months. Because this antigen is expressed by most melanoma tumors, this procedure should be useful for checking the efficiency of adoptive immunotherapy of melanoma tumors and using functionally well-defined Melan-A/MART-1-specific CTLs in a large group of patients.

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