This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by O'Mahony, D. Articles by Janik, J. E. Search for Related Content PubMed PubMed Citation Articles by O'Mahony, D. Articles by Janik, J. E. Related Collections Commentary

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?

Emmanuel M. Gabriel and Edmund C. Lattime
Clin. Cancer Res. 2007 13: 785-788. [Full Text] [PDF]

This article has been cited by other articles:

				B. Kavanagh, S. O'Brien, D. Lee, Y. Hou, V. Weinberg, B. Rini, J. P. Allison, E. J. Small, and L. Fong CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion Blood, August 15, 2008; 112(4): 1175 - 1183. [Abstract] [Full Text] [PDF]

				M. R. Goldstein, L. Mascitelli, and F. Pezzetta How Statins May Increase Prostate Cancer Cancer Epidemiol. Biomarkers Prev., February 1, 2008; 17(2): 459 - 459. [Full Text] [PDF]

				E. Degl'Innocenti, M. Grioni, G. Capuano, E. Jachetti, M. Freschi, M. T.S. Bertilaccio, R. Hess-Michelini, C. Doglioni, and M. Bellone Peripheral T-Cell Tolerance Associated with Prostate Cancer Is Independent from CD4+CD25+ Regulatory T Cells Cancer Res., January 1, 2008; 68(1): 292 - 300. [Abstract] [Full Text] [PDF]

				X. Zang and J. P. Allison The B7 Family and Cancer Therapy: Costimulation and Coinhibition Clin. Cancer Res., September 15, 2007; 13(18): 5271 - 5279. [Abstract] [Full Text] [PDF]

				E. M. Gabriel and E. C. Lattime Anti-CTL-Associated Antigen 4: Are Regulatory T Cells a Target? Clin. Cancer Res., February 1, 2007; 13(3): 785 - 788. [Full Text] [PDF]

				S. S. Neelapu and L. W. Kwak Vaccine Therapy for B-Cell Lymphomas: Next-Generation Strategies Hematology, January 1, 2007; 2007(1): 243 - 249. [Abstract] [Full Text] [PDF]