Abstract
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. 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. 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. 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.
Highlights
T-cell–mediated immunotherapy holds great potential for the treatment of human malignancies
The main target and effector cells of the CTLA-4 blockade treatment in the studied tumor models are tumor-specific endogenous CD8þ T cells that are capable of eradicating distant tumors, whereas CD4þ T cells do not play a prominent role in the antibody-mediated tumor eradication
We show that local injection of a CTLA-4 blocking antibody in the slow-release formulation Montanide ISA-51 in tumor bearing mice leads to an effective antitumor CD8þ T-cell response and tumor eradication, whereas levels of systemic antibody in serum remain low
Summary
T-cell–mediated immunotherapy holds great potential for the treatment of human malignancies. A crucial element of this therapy is the ability of CD8þ T cells (CTLs), to recognize and kill tumor cells that express tumor-associated antigens [1, 2]. Even though spontaneous tumor-specific CD8þ T-cell responses have been found, Authors' Affiliations: 1Department of Immunohematology and Blood Transfusion, Leiden University Medical Center; and 2ISA Pharmaceuticals, Leiden, the Netherlands. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Several factors, such as insufficient dendritic cell activation and antigen availability, and tumor-induced immune suppression limit these responses [3, 4]. Therapeutic interventions aimed at enhancing the efficacy of antitumor CD8þ T-cell responses are necessary to achieve clinical efficacy
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