P2.04-44 Combined Immune Checkpoint Blockade in Mesothelioma: In Vivo Investigation of in Vitro Data

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal, highlighting the urgent need for new therapeutic strategies. Our group and others have recently demonstrated PD-1 and PD-L1 expression in MPM patients, providing rationale to evaluate their suitability as immunotherapeutic targets in MPM. Tree human cell lines representative for the epithelioid and sarcomatoid subtypes of MPM were placed in allogeneic co-cultures with healthy donor peripheral blood mononuclear cells. The co-cultures were treated with the following immune checkpoint blocking antibodies: anti PD-1 (Nivolumab®, BMS) or anti PD-L1 (Durvalumab®, AstraZeneca) in combination with anti TIM-3 or anti LAG-3. Supernatant was collected and enzyme-linked immunosorbent assays and multiplex electrochemo-luminescence were used to look at the secretion of 7 cytokines, being IFNγ, IL-2/5/6/10, IL-1band TNF-α, as well as the enzyme granzyme B. Significant differences were found for the secretion of IFNγ, granzyme B, IL-2, IL-5 and IL-10. Though the differences were not always significant for the 3 MPM cell lines, the same trends were observed among them. Interestingly, highest concentrations of the aforementioned cytokines were all noticed for monotherapy treatment with anti PD-1, anti PD-L1 or or their combination with anti TIM-3. In vivo investigation of PD-1, PD-L1 and TIM-3 blockade, alone or in combination is required for validation of our in vitro results and is currently ongoing. Our data show that treatment with anti PD-1, anti PD-L1 or their respective combination with anti TIM-3 resulted in the highest secretion of cytokines and granzyme B, suggesting that these treatments stimulate the antitumor response the most. Results of our in vivo validation are awaited in order to confirm our in vitro findings.