974. PD-1 Immune Checkpoint Blockade Improves Survival and Promotes Fungal Clearance in an Immunosuppressed Murine Invasive Pulmonary Aspergillosis (IPA) Model

Abstract

BackgroundCheckpoint blockade (CPB) has brought a revolution in modern oncology and may offer new strategies for antifungal immunotherapy. In vitro studies have demonstrated that blockade of the PD-1/PDL-1 interaction increased IFN-γ secretion in response to Aspergillus antigens, suggesting a potential role for anti-PD-1 therapy in promoting anti-Aspergillus immunity. We sought to evaluate the therapeutic efficacy of low-dose anti-PD-1 therapy in a murine IPA model.MethodsEight- to twelve-week-old female BALB/c mice were immunosuppressed with cyclophosphamide and cortisone acetate and infected intra-nasally with 5 × 104 of A. fumigatus Af293 conidia (panel A). Mice were then treated intraperitoneally with 4 doses of either 200 µL PBS (PBS control), 250 µg/kg BW IgG antibody (isotype control), or a monoclonal PD-1 antibody (anti-PD-1). Survival was monitored daily until day 8 post-infection. 24–28 mice per treatment were assessed in 3 independent experiments. Pulmonary fungal burden was determined by 18S qPCR either on day 8 post-infection or upon death. Additional mice were sacrificed on day 1 and 4 post-infection to assess serum concentrations of selected cytokines by ELISA.ResultsInfected mice receiving treatment with either PBS or the isotype antibody exhibited 8 day survival rates of 33% and 36%, respectively. In contrast, 68% of the mice in the PD-1 antibody treatment group survived (panel B). Accordingly, pulmonary fungal burden was significantly reduced in anti-PD-1 vs. isotype-treated infected mice (median spore equivalent: 0.39 vs. 2.06 × 109, P = 0.015). No signs of toxicity or early mortality were seen in anti-PD-1-treated mice, and no elevated serum levels of pro-inflammatory cytokines TNF-α and INF-γ were found in those mice (compared with isotype-treated infected mice).ConclusionWe found that anti-PD-1 immune checkpoint blockade has independent beneficial effects in untreated immunosuppressed mice with IPA. We are in the process of measuring pulmonary cytokines to deepen our understanding of protective anti-Aspergillus immunity conferred by low-dose CPB. In addition, future studies would address the combined application of CPB and conventional antifungal drugs that have immune-regulatory activity such as echinocandins. Disclosures All Authors: No reported Disclosures.