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Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.

Abstract：

BACKGROUND:Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma. METHODS:Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses). RESULTS:Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis. CONCLUSIONS:There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.

journal_name

Ann Surg Oncol

journal_title

Annals of surgical oncology

authors

Maker AV,Phan GQ,Attia P,Yang JC,Sherry RM,Topalian SL,Kammula US,Royal RE,Haworth LR,Levy C,Kleiner D,Mavroukakis SA,Yellin M,Rosenberg SA

doi

10.1245/ASO.2005.03.536

keywords:

subject

Has Abstract

pub_date

2005-12-01 00:00:00

pages

1005-16

issue

eissn

1068-9265

issn

1534-4681

journal_volume

pub_type

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Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.