465 Synergistic approach to overcome the solid tumor microenvironment of mesothelioma with natural killer cell-focused immunotherapy

Abstract

Background Mesothelioma is a rare, but aggressive cancer that occurs in cells that surround internal organs. Immune check-point inhibitors (ICI) have been approved for the treatment of mesothelioma (nivolumab, ipilimumab and pembrolizumab), but currently approved strategies do not make use of natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC) of mesothelioma cells. We hypothesized that combining IL-15 treatment with an anti-PDL1 ICI that drives ADCC will enhance NK cell control of mesothelioma and lead to more robust immune control of the disease. Methods In vitro assays challenged NK cells with three pleural mesothelioma lines, H2373, H2461 and H2596 and four peritoneal mesothelioma lines, ROB, HAY and Flow cytometry was used to assess degranulation and cytokine pro-duction by NK cells co-cultured with mesothelioma cells in short-term assays (5 hours). The tumor cells were treated overnight with IFN g to mimic the inflammatory tumor microenvironment. Natural cytotoxicity was compared with ICI that do not drive ADCC (pembrolizumab), ICI that drive ADCC (avelumab) and IL-15, alone or in combination. Live cell imaging was used to track mesothelioma survival in three dimensional spheroids over 5 days when treated with NK cells and these drugs. NK cell natural cytotoxicity, H2373 H2596 sensitive. resistant