Faculty Bibliography

Malignant pleural mesothelioma (MPM) is an uncommon but aggressive and treatment resistant neoplasm with low survival rates. In the last years we assisted to an exponential growth in the appreciation of mesothelioma pathobiology, leading several new treatments to be investigated both in the early stage of the disease and in the advanced setting. In particular, expectations are now high that immunotherapy will have a leading role in the next years. However, caution is required as results from phase II studies in MPM were often not replicated in larger, randomized, phase III trials. In this review, we describe the most promising emerging therapies for the treatment of MPM, discussing the biological rationale underlying their development as well as the issues surrounding clinical trial design and proper selection of patients for every treatment.

Treatment of mesothelioma is evolving, with recent randomised trial data supporting the addition of bevacizumab to pemetrexed and cisplatin therapy. Single-agent immune checkpoint inhibitors have failed to demonstrate survival benefits in randomised trials; however, using a combination of programmed death receptor/ligand 1 (PD-(L)1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonists may be more effective. Use of immunotherapy agents in the front-line setting may also yield better results. Other immunotherapeutic approaches, such as oncolytic viruses and chimeric antigen receptor (CAR) T-cells, are progressing closer to evaluation in full-scale clinical trials, as are targeted agents, particularly those focussed on mesothelin. Arginine deprivation may be effective in patients with poor prognosis, non-epithelioid tumours. It is likely that the next decade will yield substantial progress, and the future of mesothelioma treatment looks more hopeful than it has for decades.
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SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30

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.

Malignant pleural mesothelioma is a rare cancer associated with asbestos exposure and portends a dismal prognosis. Its worldwide incidence has been increasing, and treatment options are currently suboptimal and noncurative. However, since the turn of the century, several encouraging steps have been made toward improving outcomes for mesothelioma patients. An increased understanding of disease pathophysiology has led to more accurate diagnosis and staging, and the establishment of the standard of care first-line pemetrexed/platin doublet chemotherapy regimen in 2003 initially revolutionized treatment. While significant debate remains regarding the preferred approach to surgical and radiation therapy in the context of multimodal therapy, recent breakthroughs in immunotherapy offer hope for another paradigm shift in the near future. This review will summarize the current clinical approach to diagnosis, staging, and treatment of malignant pleural mesothelioma.

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.

Malignant pleural mesothelioma (MPM) is a highly aggressive disease, with few, if any, curative interventions. While there is growing interest in using immunotherapy and immuno-gene therapy to treat MPM, very limited data currently exist for combining these modalities with radiotherapy. Preclinical data suggest that radiotherapy may be combined with immunotherapy to produce disease regression, with abscopal effects in mice with MPM. We report the first-ever case of abscopal effect in a patient with MPM, following radiotherapy and immuno-gene therapy. The patient was a 67-year-old male with prior asbestos exposure who presented with progressive dyspnea and thoracic pain. He underwent partial right pleurectomy, pleural biopsy, and talc pleurodesis, with pathology revealing epithelioid MPM. A subsequent chest computed tomography (CT) scan and fluoro-deoxyglucose positron-emission tomography (FDG-PET) CT scan showed extensive, right-sided, fluoro-deoxyglucose (FDG) avid mass-like pleural thickening encasing the right lung, with likely mediastinal extension, nodal metastases, and vascular compression. He enrolled in a clinical trial in which he received intrapleural interferon-alpha gene therapy but needed to discontinue therapy due to supraventricular tachycardia and superior vena cava syndrome induced from tumor burden. He was emergently treated with palliative radiotherapy to 30 Gy in 10 fractions. He was then started on pemetrexed and cisplatin chemotherapy. His subsequent chest CT scan two months after radiotherapy completion showed a dramatic treatment response within, as well as outside of, the irradiated field. After completion of radiotherapy, he did experience radiation esophagitis requiring nasogastric tube placement. Herein, we highlight the feasibility and efficacy of combining immuno-gene therapy with palliative radiotherapy to produce a substantial treatment response and an abscopal effect in a patient with unresectable MPM.

Lung cancer remains the leading cause of cancer death worldwide1. With new treatment modalities, there has been a shift in focus to how we can predict who may respond to targeted treatments. Current data suggest that the human microbiome can affect lung cancer treatment through its effects on the systemic immune tone. Our group has shown that the lower airway microbiota of lung cancer patients is characterized by enrichment with oral commensals2 which triggers transcriptomic signatures (PI3K, MAPK) previously described in NSCLC 2,3. The impact of local lung dysbiosis on lung cancer progression and survival is unknown. Patients with suspicious nodules on imaging who underwent bronchoscopy were recruited. High-throughput sequencing of bacterial 16S rRNA-encoding gene amplicons was performed. Clustering was based on Dirichlet-Multinomial mixtures (DMM) modeling. RNAseq was performed on bronchial epithelial cells obtained by airway brushing. We focused our analysis on 83 NSCLC samples. Overall alpha-diversity showed that advanced stage (IIIb-VI) lower airway samples were more similar to buccal samples than local stage (I-IIIa), p<0.0001. In addition, worse 6-month and 1-year survival was associated with more similar alpha-diversity between lower airway and buccal samples (Figure 1A-D). Utilizing DMM two clusters were identified, Supraglottic-Predominant-Taxa (SPT) and Background-Predominant-Taxa (BPT). There was a significant increase in percentage of SPT in advance stage compared to local stage (p<0.008) Kaplan-Meir survival analysis shows worse survival in those with NSCLC who were clustered into the SPT group compared to BPT (p=0.0003, Figure 1E). With RNAseq, differentially expressed genes between advanced stage vs. local stage and 6-month vs. 1-year survival were not as pronounced as SPT vs. BPT (Figure 1F) suggesting that globally, transcriptomic changes between different stage and NSCLC survival were difficult to detect as compared to when airway microbiome were differentiated. In lung cancer, dysbiosis within the lower airway microenvironment, possibly by micro-aspiration, is associated with a worse 6-month and 1-year survival. This change is also associated with transcriptome changes in the local environment