Abstract
Intratumoral therapy with oncolytic viruses is increasingly being explored as a strategy to potentiate an immune response against cancer, but it remains unknown whether such therapy should be restricted to cancers sensitive to virus-mediated lysis. Using Newcastle Disease Virus (NDV) as a model, we explore immunogenic potential of an oncolytic virus in bladder cancer, where existing immunotherapy with PD-1 and PD-L1-targeting antibodies to date has shown suboptimal response rates. Infection of human and mouse bladder cancer cells with NDV resulted in immunogenic cell death, activation of innate immune pathways, and upregulation of MHC and PD-L1 in all tested cell lines, including the cell lines completely resistant to NDV-mediated lysis. In a bilateral flank NDV-lysis-resistant syngeneic murine bladder cancer model, intratumoral therapy with NDV led to an increase of immune infiltration in both treated and distant tumors and a shift from an inhibitory to effector T cell phenotype. Consequently, combination of intratumoral NDV with systemic PD-1 or CTLA-4 blockade led to improved local and abscopal tumor control and overall survival. These findings encourage future clinical trials combining intratumoral NDV therapy with systemic immunomodulatory agents and underscore the rationale for such treatments irrespective of tumor cell sensitivity to NDV-mediated lysis.
Highlights
Bladder cancer is the most frequent malignancy of the urinary tract with 79,030 new cases and 16,870 deaths estimated in the United States in 2017 [1]
Using Newcastle Disease Virus (NDV) as a model, we explore immunogenic potential of an oncolytic virus in bladder cancer, where existing immunotherapy with PD-1 and PD-L1-targeting antibodies to date has shown suboptimal response rates
Immunogenic effects of NDV in bladder cancer cells are independent of its lytic potential To examine the sensitivity of bladder cancer cells to NDV-mediated lysis, 13 different human bladder cancer cell lines were treated for 24 h with NDV at a multiplicity of infection (MOI) of 2 and assessed for viability using MTT proliferation assay (Figure 1A, 1B)
Summary
Bladder cancer is the most frequent malignancy of the urinary tract with 79,030 new cases and 16,870 deaths estimated in the United States in 2017 [1]. The conversion of the tumor microenvironment by OVs to a more favorable state can improve with the immunomodulatory effects of immune checkpoint blockade, as demonstrated in recent phase I and II trials that showed both, promising response rates as well as acceptable toxicity in combination treatments of OVs with either anti-CTLA4 or anti-PD1 therapy [20,21,22]. These findings bring up the question of whether locoregional/intratumoral therapy with OVs could be used to potentiate the efficacy of systemic immune checkpoint blockade in bladder cancer
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