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

Luuk van Hooren, Linda C Sandin, Igor Moskalev, Peter Ellmark, Anna Dimberg, Peter Black, Thomas H Tötterman, Sara M Mangsbo
European Journal of Immunology2016
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 MB49 bladder carcinoma in C57BL/6 mice. When MB49 tumors were grown subcutaneously, peritumoral injection of anti-CTLA-4 treatment was equally effective as intravenous or subcutaneous (non-tumor bearing flank) administration. Notably, peritumoral 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 >10-fold reduction in systemic antibody levels as compared to intravenous or subcutaneous 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, peritumoral anti-CTLA-4 therapy was potentiated by depletion of regulatory T (Treg) 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.

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