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

Authors' Affiliations: ¹ University of California, San Francisco, San Francisco, California; ² Pacific Shores Medical Group, Long Beach, California; ³ Cleveland Clinic Taussig Cancer Center, Cleveland, Ohio; ⁴ Medarex Corporation, Bloomsbury, New Jersey; and ⁵ Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Eric J. Small, UCSF Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero Street, 3rd Floor, San Francisco, CA 94115. Phone: 415-353-7095; Fax: 415-353-7779; E-mail: smalle{at}medicine.ucsf.edu.

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.

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