title: Controlled local delivery of CTLA-4 blocking antibody induces CD8+ T-cell-dependent tumor eradication and decreases risk of toxic side effects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center; and ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Marieke F
authors.initials: MF
authors.lastname: Fransen
authors.forename: Tetje C
authors.initials: TC
authors.lastname: van der Sluis
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen