[Ipilimumab after Cancer Vaccine Failure in Patients with Advanced Malignancy]
>>Clinical Cancer Research 13, 958-964, February 1, 2007
A Pilot Study of CTLA-4 Blockade after Cancer Vaccine Failure in Patients with Advanced Malignancy
Deirdre O'Mahony1, John C. Morris1, Cate Quinn1, Wendy Gao1, Wyndham H. Wilson1, Barry Gause2, Stefania Pittaluga3, Sattva Neelapu2, Margaret Brown4, Thomas A. Fleisher4, James L. Gulley2, Jeffrey Schlom5, Robert Nussenblatt6, Paul Albert7, Thomas A. Davis8, Israel Lowy8, Mike Petrus1, Thomas A. Waldmann1 and John E. Janik1
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@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.<<
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