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A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy

Authors' Affiliations: ¹ Metabolism Branch, ² Medical Oncology Branch, ³ Laboratory of Pathology, ⁴ Department of Laboratory Medicine, ⁵ Laboratory of Tumor Immunology and Biology, ⁶ National Eye Institute, and ⁷ Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland and ⁸ Medarex, Inc., Bloomsbury, New Jersey

Requests for reprints: John E. Janik, Metabolism Branch, Center for Cancer Research, National Cancer Institute, Room 4E-5330, Bethesda, MD 20892-1457. Phone: 301-402-2913; Fax: 301-402-1001; E-mail: janikj{at}mail.nih.gov.

Purpose: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8⁺ T-cell immune responses, and modulation of CD4⁺ CD25⁺ FoxP3⁺ regulatory T-cell (Treg) numbers were secondary end points.

Experimental Design: Three patients with colon cancer, four with non–Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.

Results: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4⁺CD25 ⁺CD62L ⁺ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.

Conclusions: Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8⁺ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.

Commentary

Anti–CTL-Associated Antigen 4: Are Regulatory T Cells a Target?

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