Abstract
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.
MeSH terms
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Adult
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Antibodies, Monoclonal / adverse effects
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Neoplasm / adverse effects
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Antibodies, Neoplasm / immunology
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Antibodies, Neoplasm / therapeutic use*
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Antigens, CD
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Antigens, Differentiation / immunology*
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Antigens, Differentiation / physiology
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Antigens, Neoplasm / administration & dosage
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Antigens, Neoplasm / immunology*
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Autoimmune Diseases / etiology*
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Autoimmune Diseases / immunology
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Autoimmune Diseases / pathology
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CTLA-4 Antigen
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Colitis / etiology
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Colitis / immunology
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Colitis / pathology
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Dermatitis / etiology
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Dermatitis / immunology
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Dermatitis / pathology
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Female
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HLA-A2 Antigen / immunology
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Hepatitis, Autoimmune / etiology
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Hepatitis, Autoimmune / immunology
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Hepatitis, Autoimmune / pathology
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Humans
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Immune Tolerance / immunology
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Immunotherapy*
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Injections, Intravenous
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Injections, Subcutaneous
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Lymphocyte Activation
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Male
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Melanoma / immunology
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Melanoma / therapy*
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Membrane Glycoproteins / chemistry
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Membrane Glycoproteins / immunology*
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Middle Aged
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Neoplasm Metastasis
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / immunology*
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology*
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Peptides
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Salvage Therapy
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Cytotoxic / immunology*
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Vaccination*
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Vitiligo / etiology
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Vitiligo / immunology
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Vitiligo / pathology
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gp100 Melanoma Antigen
Substances
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Antibodies, Monoclonal
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Antibodies, Neoplasm
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Antigens, CD
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Antigens, Differentiation
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Antigens, Neoplasm
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CTLA-4 Antigen
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CTLA4 protein, human
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HLA-A2 Antigen
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Membrane Glycoproteins
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Neoplasm Proteins
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PMEL protein, human
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Peptide Fragments
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Peptides
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gp100 Melanoma Antigen
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gp100(280-288) melanoma antigen peptide