title: A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer.
abstract: OBJECTIVE
  Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongs T-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab.
  
  
  METHODS
  Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken.
  
  
  RESULTS
  Fourteen patients were treated: 12 patients received a single dose of Ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression. Two patients showed PSA declines of > or =50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritus requiring systemic corticosteroids. The mean +/- SD Ipilimumab terminal elimination half-life was 12.5 +/- 5.3 days.
  
  
  CONCLUSIONS
  A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. PSA-modulating effects observed warrant further investigation.
authors.affiliation: UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94115, USA. smalle@medicine.ucsf.edu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
authors.forename: N Simon
authors.initials: NS
authors.lastname: Tchekmedyian
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000943:Antigens, Differentiation / Q000276:immunology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D060908:CTLA-4 Antigen; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; D017430:Prostate-Specific Antigen