A Pilot Trial of CTLA-4 Blockade with Human Anti-CTLA-4 in Patients with Hormone-Refractory Prostate Cancer

• Published in: Clinical cancer research 2007-03, Vol.13 (6), p.1810-1815
• Main Authors: SMALL, Eric J, TCHEKMEDYIAN, N. Simon, RINI, Brian I, FONG, Lawrence, LOWY, Israel, ALLISON, James P
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - immunology; Aged; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antigens, CD - immunology; Antigens, Differentiation - immunology; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; CTLA-4 Antigen; Drug Resistance, Neoplasm - drug effects; Gynecology. Andrology. Obstetrics; hormone refractory prostate cancer; Humans; Immune System - drug effects; Ipilimumab; Male; Male genital diseases; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Pilot Projects; Prostate-Specific Antigen - analysis; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - immunology; PSA modulation; T cell responses; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-2318

Purpose: 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. Experimental Design: 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 ≥50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritis 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.