Faculty Bibliography

Malignant pleural effusions (MPE) complicate malignancies and portend worse outcomes. MPE is comprised of various components, including immune cells, cancer cells, and cell-free DNA/RNA. There have been investigations into using these components to diagnose and prognosticate MPE. We hypothesize that the microbiome of MPE is unique and may be associated with diagnosis and prognosis. We compared the microbiota of MPE against microbiota of pleural effusions from non-malignant and paramalignant states. We collected a total of 165 pleural fluid samples from 165 subjects; Benign (n = 16), Paramalignant (n = 21), MPE-Lung (n = 57), MPE-Other (n = 22), and Mesothelioma (n = 49). We performed high throughput 16S rRNA gene sequencing on pleural fluid samples and controls. We showed that there are compositional differences among pleural effusions related to non-malignant, paramalignant, and malignant disease. Furthermore, we showed differential enrichment of bacterial taxa within MPE depending on the site of primary malignancy. Pleural fluid of MPE-Lung and Mesothelioma were associated with enrichment with oral and gut bacteria that are commonly thought to be commensals, including Rickettsiella, Ruminococcus, Enterococcus, and Lactobacillales. Mortality in MPE-Lung is associated with enrichment in Methylobacterium, Blattabacterium, and Deinococcus. These observations lay the groundwork for future studies that explore host-microbiome interactions and their influence on carcinogenesis.

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with low survival rates. Platinum-based chemotherapy has represented the cornerstone of treatment for over a decade, prompting the investigation of new therapeutic strategies both in the early stage of the disease and in the advanced setting. The advent of immune check-point inhibitors (ICIs) has recently revamped the enthusiasm for using immunotherapy also in MPM. However, results from first clinical trials using single immune check-point inhibition have been conflicting, and this may be mainly attributed to the lack of specific biomarkers as well as to intra- and inter- patient heterogeneity. The phase III Checkmate743 firstly demonstrated the superiority of an ICI combination (nivolumab plus ipilimumab) over chemotherapy in the first-line treatment of unresectable MPM, leading to FDA approval of this regimen and showing that moving beyond single immune check point inhibition might be a successful strategy to overcome resistance in the majority of MPM patients. In this review, we describe the emerging immunotherapy strategies for the treatment of MPM. We also discuss how refining the approach in pre-clinical studies towards a more holistic perspective (which takes into account not only genetic but also pathophysiological vulnerabilities) and strengthening multi-institutional collaboration in clinical trials is finally helping the clinical development of immunotherapy in MPM.

OBJECTIVES/OBJECTIVE:Tumor draining lymph nodes (TDLN) are key sites of early immunoediting in patients with non-small cell lung cancer (NSCLC) and play an important role in generating anti-tumor immunity. Immune suppression in the tumor microenvironment has prognostic implications and may predict therapeutic response. T cell composition of draining lymph nodes may reflect an immunophenotype with similar prognostic potential which could be measured during standard-of-care bronchoscopic assessment. In this study, we compared the immunophenotype from different sites within individuals to primary tumor characteristics in patients with NSCLC to see whether there were tumor-regional differences in immunophenotype which could be evaluated from transbronchial needle aspirates. MATERIALS AND METHODS/METHODS:Twenty patients were enrolled in this study and had tissue (lymph node aspirates and/or peripheral blood) obtained during standard of care bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis or staging of known or suspected NSCLC. Aspirates and blood underwent flow-assisted cell sorting and a subset of sorted effector T cells underwent RNA quantitation to determine feasibility of this approach. Immunophenotypic patterns from twelve patients with paired data from tumor-draining and non-tumor draining lymph nodes (NDLN) were compared relative to one another and based on PD-L1 immunohistochemistry and primary tumor histology. RESULTS: T cell depletion compared to patients with PD-L1 expression <50% (-35.98% vs -1.89%, p = 0.0357; negative values represent absolute difference between paired TDLN and NDLN). CONCLUSIONS:In patients with NSCLC, TDLN have a suppressive immunophenotype correlating with tumor PD-L1 status and can be assessed during routine EBUS-TBNA.

OBJECTIVES/OBJECTIVE:Malignant pleural mesothelioma and malignant pleural effusions are a major therapeutic challenge, and are associated with impairment in quality of life and increased mortality. Advances in systemic therapies of malignant pleural mesothelioma have demonstrated limited clinical benefit and there is ongoing interest in intrapleural immunotherapies which have been demonstrated to be well-tolerated overall with variable clinical responses. We have reviewed the literature to provide a comprehensive summary of novel intrapleural immunotherapeutic paradigms, including oncolytic virus therapy, gene-mediated cytotoxic immunotherapy, direct cytokine-mediated immunotherapies, innate immunomodulators, and adoptive transfer of intrapleural chimeric antigen receptor T-cell therapy. DATA SOURCES/METHODS:A review of PubMed for original manuscripts and conference reports published between 1998 and 2018 pertaining to intrapleural immunotherapy, as well as examination of reference lists from reviewed manuscripts. STUDY SELECTION/METHODS:Human clinical trials on intrapleural immunotherapies in subjects with malignant pleural mesothelioma or malignant pleural effusion were included in this review, including some relevant pre-clinical studies and anticipated ongoing trials reported on Clinicaltrials. gov. RESULTS:26 clinical trials were identified, in addition to three trials currently in progress. CONCLUSION/CONCLUSIONS:Intrapleural immunotherapies for pleural malignancy have demonstrated promise with regards to generating durable tumor-specific immune responses with possible clinical benefits which merit further investigation as part of multimodal chemo- and immunotherapeutic regimens.

BACKGROUND:In lung cancer, upregulation of the PI3K pathway is an early event that contributes to cell proliferation, survival, and tissue invasion. Upregulation of this pathway was recently described as associated with enrichment of the lower airways with bacteria identified as oral commensals. We hypothesize that host-microbe interactions in the lower airways of subjects with lung cancer affect known cancer pathways. METHODS:Airway brushes were collected prospectively from subjects with lung nodules at time of diagnostic bronchoscopy, including 39 subjects with final lung cancer diagnoses and 36 subjects with non-cancer diagnosis. Additionally, samples from 10 healthy control subjects were included. 16S rRNA gene amplicon sequencing and paired transcriptome sequencing (RNAseq) were performed on all airway samples. In addition, an in vitro model with airway epithelial cells exposed to bacteria/bacterial products was performed. RESULTS:The composition of the lower airway transcriptome in the cancer patients was significantly different from the controls, which included upregulation of ERK and PI3K signaling pathways. The lower airways of lung cancer patients were enriched for oral taxa (Streptococcus and Veillonella), which was associated with upregulation of the ERK and PI3K signaling pathways. In vitro exposure of airway epithelial cells to Veillonella, Prevotella, and Streptococcus led to upregulation of these same signaling pathways. CONCLUSIONS:The data presented here shows that several transcriptomic signatures previously identified as relevant to lung cancer pathogenesis are associated with enrichment of the lower airway microbiota with oral commensals.

Zika virus (ZIKV) infection has been associated with Guillain-Barré Syndrome (GBS). Roughly 60% of people in countries such as the U.S. live in areas at risk for seasonal spread of ZIKV. ZIKV belongs to a class of diseases that is not typically seen in hospital settings across the U.S. and Europe. We describe the case presentation, management, and treatment of ZIKV infection complicated by GBS. A 64-year-old woman with recent travel to the Dominican Republic presented with rash followed by an acute, ascending polyneuropathy consistent with GBS. She was confirmed to have an acute ZIKV infection by detection of ZIKV nucleic acid by reverse transcription-polymerase chain reaction. She met Brighton Collaboration criteria level 1 evidence for GBS. She received two courses of intravenous immunoglobulin and slowly improved, though still had weakness at discharge. More research is needed to identify the pathophysiology behind ZIKV-associated GBS and its optimal treatment. Prevention is fundamental to limiting infection and spread of ZIKV.

Pleural malignancies remain a serious therapeutic challenge, and are frequently refractory to standard treatment; however, they have the advantage of occurring in an enclosed cavity readily accessible for examination, biopsy, and serial sampling. Novel therapeutics can be administered via intracavitary delivery to maximize efficacy by targeting the site of involvement and potentially mitigating the adverse effects of systemic therapies. The easy accessibility of the pleural space lends itself well to repeated sampling and analysis to determine efficacy and toxicity of a given treatment paradigm. These factors support the rationale for delivery of novel therapeutics directly into the pleural space.