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Brief Definitive Report

Cassian Yee^a,b, John A. Thompson^b, Patrick Roche^d, David R. Byrd^c, Peter P. Lee^e, Michael Piepkorn^b, Karla Kenyon^a, Mark M. Davis^e, Stanley R. Riddell^a,b, and Philip D. Greenberg^a,b

^a Clinical Research Division, Fred Hutchinson Cancer Research Center, the
^b Department of Medicine, University of Washington, Seattle, Washington 98109
^c Department of Surgery, University of Washington, Seattle, Washington 98109
^d Department of Pathology, Mayo Clinic, Rochester, Minnesota 55905
^e Department of Microbiology and Immunology, Stanford University, Stanford, California 94305
the Fred Hutchinson Cancer Research Center, D3-100, 1100 Fairview Ave. N., Seattle, WA 98109.206-667-7983206-667-6287

cyee{at}fhcrc.org

Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1–specific CD8⁺ T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell–specific peptide–major histocompatibility complex tetramers demonstrated a localized predominance of MART-1–specific CD8⁺ T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.

Key Words: immunotherapy • melanoma • autoimmunity • vitiligo • T lymphocytes

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