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Clin Cancer Res. 2013 Oct 1;19(19):5381-9. doi: 10.1158/1078-0432.CCR-12-0781. Epub 2013 Jun 20.

Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects.

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1
Authors' Affiliations: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center; and ISA Pharmaceuticals, Leiden, the Netherlands.

Abstract

PURPOSE:

Blockade of CTLA-4 by antibodies has potentiated antitumor T-cell responses in both preclinical models and clinical trials. However, treatment with CTLA-4 blocking antibodies is associated with autoimmune and inflammatory side effects. In this study, we propose a novel administration method for CTLA-4 blocking antibodies as monotherapy.

EXPERIMENTAL DESIGN:

We use different preclinical mouse models of cancer to investigate the local administration of CTLA-4 blocking antibody and its effect on cancer progression and the antitumor T-cell response.

RESULTS:

By injecting the antibodies in a subcutaneous slow-release delivery formulation in the tumor area, we show that an eight-fold lower dose of antibody is as effective in inducing tumor eradication as systemic delivery. A lower dose and slow release of the antibody results in thousand-fold decreased levels of antibody in the serum, reducing adverse events and the risk of autoimmunity. The main target and effector cells of the CTLA-4 blockade treatment in the studied tumor models are tumor-specific endogenous CD8(+) T cells that are capable of eradicating also distant tumors, whereas CD4(+) T cells do not play a prominent role in the antibody-mediated tumor eradication.

CONCLUSIONS:

Injecting CTLA-4 blocking antibody in a slow-release formulation close to the tumor is an effective way of activating the antitumor T-cell response. This administration method is associated with very low serum levels of antibody, which decreases the risk of treatment-induced side effects. These results call for exploration of a similar delivery principle in clinical settings.

PMID:
23788581
DOI:
10.1158/1078-0432.CCR-12-0781
[Indexed for MEDLINE]
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