Intrapleural immunotherapeutic nanoparticles for MPE treatment

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Abstract Malignant pleural effusion (MPE) secondary to non-small cell lung cancer (NSCLC) represents a significant challenge in clinical patient management. MPE is commonly indicative of late stage malignancy and prognosis of MPE is extremely poor, with a median survival between 4-9 months. The presence of MPE often precludes surgical intervention, and many patients with MPE are not fit for chemotherapy due to the extremely poor condition. Current standard of care treatment for MPE is largely palliative. Significant clinical evidence suggests that the tumor immune microenvironment (TIME) of MPE is profoundly immunosuppressive with abundant tumor- promoting phenotype of immune cells, which impacts negatively on antitumor immunity. Previous attempts to improve the TIME involving intrapleural administration of immunotherapeutics have led to some degree of efficacy. The recent advent of immunotherapy with immune checkpoint blockade (ICB) has aroused renewed interest in seeking an effective strategy to mitigate the immune cold MPE to enhance the ICB immunotherapy. Stimulators of interferon genes (STING) pathway has recently been identified to play an important role on induction of antitumor immunity. As a potent STING agonist, cGAMP ligates STING in cytosol to activate type I interferons (IFNs) production. However, intrinsic property of cGAMP makes it susceptible to degradation by a phosphodiesterase that exists in many tissues, and higher levels of the enzyme are identified in malignant effusions. Moreover, previous studies indicate that activation of STING within tumor–resident antigen-presenting cells (APCs) is necessary for induction of tumor-specific CD8+T cell immunity. We have recently developed a novel nanotechonological strategy for APC-targeted delivery of cGAMP (LNP-STING). We assemble LNP- STING with phosphatidylserine on the outer layer of liposome to facilitate its recognition and uptake preferably by APCs, and load cGAMP complexed with calcium phosphate to enhance both the loading efficiency and the release of cGAMP to cytosol, where it binds to STING. In this project, we propose to establish an optimal LNP- STING for intrapleural administration and test if intrapleural LNP-STING converts the immune cold into proinflammatory hot MPE. Our central hypothesis is that intrapleural LNP-STING enables to mitigate the immunosuppressive MPE, thereby setting the stage for favorable response to anti-PD-L1 ICB. We will test the combination immunotherapy in both MPE mouse models and NSCLC patients’ MPE samples. We propose to establish an optimal LNP-STING for intrapleural APC-targeted delivery of STING agonist (Aim1). We will then determine if intrapleural LNP-STING effectively mitigate the immune cold MPE (Aim2). We will last determine if intrapleural LNP-STING enhances efficacy of the ICB immunotherapy (Aim3). More importantly, we will gain insights into the biological mechanisms of intrapleural LNP-STING in combination with anti-PD-L1 ICB, which likely engage both the innate and adaptive anticancer immunity. This work is significant because it may have a potential to make an impact on the MPE immunotherapy.