title: Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer.
abstract: Checkpoint blockade of CTLA-4 results in long-lasting survival benefits in metastatic cancer patients. However, patients treated with CTLA-4 blockade have suffered from immune-related adverse events, most likely due to the breadth of the induced T-cell activation. Here, we investigated the efficacy of a local low-dose anti-CTLA-4 administration for treatment of subcutaneous or orthotopic murine bladder 49 (MB49) bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown s.c., peritumoral (p.t.) injection of anti-CTLA-4 treatment was equally effective as intravenous or s.c. (nontumor bearing flank) administration. Notably, p.t. injection was associated with lower circulating antibody levels and decreased IL-6 serum levels as compared to systemic treatment. Ultrasound-guided intratumoral anti-CTLA-4 antibody treatment of orthotopically growing MB49 tumors resulted in tumor regression, with more than tenfold reduction in systemic antibody levels as compared to i.v. or s.c. administration, in line with the compartmentally restrained nature of the bladder. Local anti-CTLA-4 therapy in combination with anti-PD-1 therapy resulted in complete responses, superior to each therapy alone. In addition, p.t. anti-CTLA-4 therapy was potentiated by depletion of regulatory T cells. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and cytokine release, and enhances the response to anti-PD1 therapy.
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Luuk
authors.initials: L
authors.lastname: van Hooren
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Sandin
authors.affiliation: Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Moskalev
authors.affiliation: Alligator Bioscience AB, Lund, Sweden.|Department of Immunotechnology, Lund University, Lund, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Ellmark
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Dimberg
authors.affiliation: Alligator Bioscience AB, Lund, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Black
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Tötterman
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Mangsbo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D006131:Growth Inhibitors / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D016207:Cytokines; D006131:Growth Inhibitors; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: Bladder cancer; CTLA-4; Checkpoint inhibitors; Immunotherapy; Local low-dose; MB49; PD-1