Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer

Research output: Contribution to journalArticle

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.

Details

Authors
  • Luuk van Hooren
  • Linda C Sandin
  • Igor Moskalev
  • Peter Ellmark
  • Anna Dimberg
  • Peter Black
  • Thomas H Tötterman
  • Sara M Mangsbo
Organisations
External organisations
  • Uppsala University
  • University of British Columbia
  • Alligator Bioscience AB
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Bladder cancer, Checkpoint inhibitors, CTLA-4, Immunotherapy, Local low-dose, MB49, PD-1
Original languageEnglish
Pages (from-to)385-393
JournalEuropean Journal of Immunology
Volume47
Issue number2
Early online date2016
Publication statusPublished - 2017 Feb
Publication categoryResearch
Peer-reviewedYes