Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
Level II
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- Record sourced from PubMed, PMID 12826605.
- Also identified by PMC identifier 166236.
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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.
Medical subject headings
- Antibodies, Monoclonal
- Antibodies, Neoplasm
- Antigens, Differentiation
- Antigens, Neoplasm
- Autoimmune Diseases
- Immunotherapy
- Melanoma
- Membrane Glycoproteins
- Neoplasm Proteins
- Peptide Fragments
- T-Lymphocyte Subsets
- T-Lymphocytes, Cytotoxic
- Vaccination