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Immunization of Stage IV Melanoma Patients with Melan-A/MART-1 and gp100 Peptides plus IFN- Results in the Activation of Specific CD8⁺ T Cells and Monocyte/Dendritic Cell Precursors

¹ Section of Experimental Immunotherapy, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità; ² Division IV of Dermatology, ³ Laboratory of Molecular Oncology, Istituto Dermopatico dell'Immacolata; and ⁴ Department of Neurosciences, University of Rome "Tor Vergata," Rome, Italy; and Unit of ⁵ Immunotherapy of Human Tumor, ⁶ Melanoma and Sarcoma, and ⁷ Immunohematology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy

Requests for reprints: Filippo Belardelli, Section of Experimental Immunotherapy, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-06-4990-3290; Fax: 39-06-49902097; E-mail: belard{at}iss.it.

The use of IFN- in clinical oncology has generally been based on the rationale of exploiting its antiproliferative and antiangiogenic activities. However, IFN- also exhibits enhancing effects on T-cell and dendritic cell functions, which may suggest a novel use as a vaccine adjuvant. We have carried out a pilot phase I-II trial to determine the effects of IFN-, administered as an adjuvant of Melan-A/MART-1:26-35(27L) and gp100:209-217(210M) peptides, on immune responses in stage IV melanoma patients. In five of the seven evaluable patients, a consistent enhancement of CD8⁺ T cells recognizing modified and native MART-1 and gp100 peptides and MART-1⁺gp100⁺ melanoma cells was observed. Moreover, vaccination induced an increase in CD8⁺ T-cell binding to HLA tetramers containing the relevant peptides and an increased frequency of CD45RA⁺CCR7^– (terminally differentiated effectors) and CD45RA^–CCR7^– (effector memory) cells. In all patients, treatment augmented significantly the percentage of CD14⁺ monocytes and particularly of the CD14⁺CD16⁺ cell fraction. An increased expression of CD40 and CD86 costimulatory molecules in monocytes was also observed. Notably, postvaccination monocytes from two of the three patients showing stable disease or long disease-free survival showed an enhanced antigen-presenting cell function and capability to secrete IP10/CXCL10 when tested in mixed leukocyte reaction assays, associated to a boost of antigen and melanoma-specific CD8⁺ T cells. Although further clinical studies are needed to show the adjuvant activity of IFN-, the present data represent an important starting point for considering a new clinical use of IFN- and new immunologic end points, potentially predictive of clinical response. (Cancer Res 2006; 66(9): 4943-51)

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