Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma.
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.
Phan
Giao Q
GQ
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yang
James C
JC
Sherry
Richard M
RM
Hwu
Patrick
P
Topalian
Suzanne L
SL
Schwartzentruber
Douglas J
DJ
Restifo
Nicholas P
NP
Haworth
Leah R
LR
Seipp
Claudia A
CA
Freezer
Linda J
LJ
Morton
Kathleen E
KE
Mavroukakis
Sharon A
SA
Duray
Paul H
PH
Steinberg
Seth M
SM
Allison
James P
JP
Davis
Thomas A
TA
Rosenberg
Steven A
SA
D000328:Adult; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000502:physiology; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen; D003092:Colitis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D003872:Dermatitis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D019693:Hepatitis, Autoimmune / Q000209:etiology / Q000276:immunology / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D010455:Peptides; D016879:Salvage Therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D014820:Vitiligo / Q000209:etiology / Q000276:immunology / Q000473:pathology; D058951:gp100 Melanoma Antigen
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D010455:Peptides; D058951:gp100 Melanoma Antigen; C548641:gp100(280-288) melanoma antigen peptide