Melanocyte destruction after antigen-specific immunotherapy of melanoma: direct evidence of t cell-mediated vitiligo.
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.
Yee
C
C
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Thompson
J A
JA
Roche
P
P
Byrd
D R
DR
Lee
P P
PP
Piepkorn
M
M
Kenyon
K
K
Davis
M M
MM
Riddell
S R
SR
Greenberg
P D
PD
D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects* / Q000379:methods; D058965:MART-1 Antigen; D008544:Melanocytes / Q000166:cytology / Q000276:immunology*; D008545:Melanoma / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000276:immunology*; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000473:pathology; D012878:Skin Neoplasms / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000145:classification / Q000276:immunology; D014820:Vitiligo / Q000209:etiology / Q000276:immunology* / Q000473:pathology
D000951:Antigens, Neoplasm; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins