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Molecular Oncology, Markers, Clinical Correlates |
Department of Surgery, Division of Surgical Oncology [L. H. B., A. R., V. B. D., S. N. A., J. S. E.], Department of Medicine, Division of Hematology/Oncology [A. R., H. T. V., D. O., J. A. G.], Department of Biomathematics [H-J. W., R. M. E.], Department of Experimental Radiation Oncology [W. H. M.], Department of Pathology and Laboratory Medicine [A. J. C.], and Department of Microbiology, Immunology and Molecular Genetics [J. S. E.], University of California Los Angeles Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California 90095-1782, and Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut [B. M.]
Purpose: The purpose of this study was to determine the toxicity and immunological effects of three different doses and two routes of administration of autologous dendritic cells (DCs) pulsed with the MART-127–35 immunodominant epitope.
Experimental Design: Eighteen HLA-A*0201-positive subjects with stage III-IV melanoma received three biweekly i.v. or intradermal injections of ex vivo generated myeloid DCs pulsed with MART-127–35 epitope. Repeated blood samples were processed to obtain peripheral blood mononuclear cells for immunological analysis using IFN-
ELISPOT, MHC class I tetramer, intracellular cytokine staining, and microcytotoxicity assays.
Results: The frequency of MART-1/Melan-A (MART-1) antigen-specific T cells in peripheral blood increased in all dose levels as assessed by ELISPOT and MHC class I tetramer assays, but without a clear dose-response effect. The intradermal route generated stronger MART-1 immunity compared with the i.v. route. MART-1-specific immunity did not correlate with clinical outcome in any of the four immunological assays used. However, analysis of determinant spreading to other melanoma antigens was noted in the only subject with complete response to this single-epitope immunization.
Conclusions: Intradermal immunization with MART-1 peptide-pulsed DCs results in an increase in circulating IFN--producing, antigen-specific T cells. The frequency of these cells did not correlate with response. In contrast, spreading of immune reactivity to other melanoma antigens was only evident in a subject with a complete response, suggesting that determinant spreading may be an important factor of clinical response to this form of immunotherapy.
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