Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.
OBJECTIVE
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) blockade with CP-675,206, a fully human anti-CTLA4 monoclonal antibody, may break peripheral immunologic tolerance leading to effective immune responses to cancer in humans. A phase I trial was conducted to test the safety of CP-675,206.


METHODS
Thirty-nine patients with solid malignancies (melanoma, n = 34; renal cell, n = 4; colon, n = 1) received an intravenous (IV) infusion of CP-675,206 at seven dose levels. The primary objective was to determine the maximum-tolerated dose and the recommended phase II dose.


RESULTS
Dose-limiting toxicities and autoimmune phenomena included diarrhea, dermatitis, vitiligo, panhypopituitarism and hyperthyroidism. Two patients experienced complete responses (maintained for 34+ and 25+ months), and there were two partial responses (26+ and 25+ months) among 29 patients with measurable melanoma. There have been no relapses thus far after objective response to therapy. Four other patients had stable disease at end of study evaluation (16, 7, 7, and 4 months). Additionally, five patients had extended periods without disease progression (36+, 35+, 26+, 24+, and 23+ months) after local treatment of progressive metastases. Longer systemic exposure to CP-675,206 achieved in higher dose cohorts predicted for a higher probability of response.


CONCLUSIONS
CP-675,206 can be administered safely to humans as a single IV dose up to 15 mg/kg, resulting in breaking of peripheral immune tolerance to self-tissues and antitumor activity in melanoma.
Ribas
Antoni
A
Department of Medicine, Division of Hematology/Oncology Surgery, University of California at Los Angeles, CA, USA.
Camacho
Luis H
LH
Lopez-Berestein
Gabriel
G
Pavlov
Dmitri
D
Bulanhagui
Cecile A
CA
Millham
Robert
R
Comin-Anduix
Begoña
B
Reuben
James M
JM
Seja
Elisabeth
E
Parker
Charla A
CA
Sharma
Amarnath
A
Glaspy
John A
JA
Gomez-Navarro
Jesus
J
D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000276:immunology / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D000951:Antigens, Neoplasm; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000276:immunology / Q000628:therapy; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D009369:Neoplasms; D012044:Regression Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology; D016896:Treatment Outcome
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins