Faculty Bibliography

In the past decade, immunotherapy has emerged as a new treatment modality in cancer. The most success has been achieved with the class of checkpoint inhibitors; antibodies which unleash the anti-tumor immune response. Following the success in melanoma, numerous clinical trials are being conducted investigating checkpoint inhibitors in lung cancer and mesothelioma. The programmed death protein 1-protein death ligand 1/2 (PD-1 - PD-L1/2) pathway and cytotoxic T-lymphocyte associated protein 4 (CTLA4) are currently the most studied immunotherapeutic targets in these malignancies. In non-small cell lung cancer (NSCLC), anti-programmed death receptor -1 (PD-1) antibodies have become part of the approved treatment arsenal. In small cell lung cancer (SCLC) and mesothelioma the efficacy of checkpoint inhibition has not yet been proven. In this concise clinical review, an overview of the landmark clinical trials investigating checkpoint blockade in lung cancer and mesothelioma is provided. Since response rates are around 20% in the majority of clinical trials, there is much room for improvement. Predictive biomarkers are therefore essential to fully develop the potential of checkpoint inhibitors. To increase efficacy, multiple clinical trials investigating the combination of CTLA4 inhibitors and PD-1/PD-L1 blockade in lung cancer and mesothelioma are being conducted or underway. Given the potential benefit of immunotherapy, implementation of current and new knowledge in trial designs and interpretation of results is essential to move forward.

RATIONALE: Transbronchial cryobiopsy is an emerging technique for obtaining biopsies of lung parenchyma. Despite limited evidence of safety and efficacy in direct comparison to other available biopsy procedures, pulmonologists are integrating this technique into clinical practice with the hope of avoiding the risks of surgical lung biopsy. OBJECTIVES: To report the rate of severe complications and diagnostic outcomes immediately after introduction of transbronchial cryobiopsy into the clinical practice of a single-center, high-volume, interventional pulmonary group at a large academic medical center in the United States. METHODS: Retrospective review of a case series. RESULTS: Twenty-five consecutive patients underwent transbronchial cryobiopsy for a variety of indications over a period of 14 weeks. In the absence of a strict protocol, a variety of techniques was employed by four attending interventional pulmonologists and one advanced interventional pulmonology fellow to plan and complete the procedures. Three patients (12%) experienced serious hemorrhage immediately after biopsy, including one patient who survived a life-threatening bleed. Two procedures were complicated by an iatrogenic pneumothorax. One patient experienced hypercapnic respiratory failure shortly after the procedure. A definitive diagnosis was made on 14 cryobiopsies (56%). Another 5 biopsies (20%) contributed to a presumptive diagnosis achieved by multidisciplinary consensus. CONCLUSIONS: Transbronchial cryobiopsy may have diagnostic and safety limitations that are not yet well appreciated given the state of the published medical literature. Major questions remain regarding the safest procedural protocol to be used when performing transbronchial cryobiopsy. Thorough planning and a high degree of caution are encouraged on first introduction of this technique into a clinical practice.

The detection of peripheral lung nodules is increasing due to expanded use of computed tomography (CT) and implementation of lung cancer screening recommendations. Although surgical resection of malignant nodules remains the treatment modality of choice at present, many patients are not surgical candidates, thus prompting the need for other therapeutic options. Stereotactic body radiotherapy (SBRT) and percutaneous thermal ablation are emerging as viable alternatives to surgical resection. For safety, efficacy, and cost-effectiveness purposes, however, alternative bronchoscopic methods for treatment of peripheral lung cancer are currently under active exploration. We searched the Cochrane Library and Medline from 1990 to 2015 to provide the most comprehensive review for bronchoscopic treatment of malignant lung nodules. We used the following search terms: bronchoscopy; lung nodule; peripheral lung lesion; and bronchoscopic treatment. We focused on peripheral pulmonary nodules that are confirmed or highly likely to be malignant. Seventy-one articles were included in this narrative review. We provide herein an overview of advanced bronchoscopic modalities that have been utilized or are under active investigation for definitive treatment of malignant pulmonary nodules. We concisely discuss the use of direct intratumoral chemotherapy or gene therapies, transbronchial brachytherapy, bronchoscopy-guided radiofrequency ablation, placement of markers to guide real time radiation and surgery, cryotherapy and photodynamic therapy. We also briefly report on emerging technologies such as vapor ablation of lung parenchyma for lung cancers. Advances in bronchoscopic therapy will bring additional treatment options to patients with peripheral lung malignancies, with putative advantages over other minimally invasive modalities.

Microaspiration is a common phenomenon in healthy subjects, but its frequency is increased in chronic inflammatory airway diseases, and its role in inflammatory and immune phenotypes is unclear. We have previously demonstrated that acellular bronchoalveolar lavage samples from half of the healthy people examined are enriched with oral taxa (here called pneumotypeSPT) and this finding is associated with increased numbers of lymphocytes and neutrophils in bronchoalveolar lavage. Here, we have characterized the inflammatory phenotype using a multi-omic approach. By evaluating both upper airway and acellular bronchoalveolar lavage samples from 49 subjects from three cohorts without known pulmonary disease, we observed that pneumotypeSPT was associated with a distinct metabolic profile, enhanced expression of inflammatory cytokines, a pro-inflammatory phenotype characterized by elevated Th-17 lymphocytes and, conversely, a blunted alveolar macrophage TLR4 response. The cellular immune responses observed in the lower airways of humans with pneumotypeSPT indicate a role for the aspiration-derived microbiota in regulating the basal inflammatory status at the pulmonary mucosal surface.

Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy-monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy.

PURPOSE: "In situ vaccination" using immuno-gene therapy has the ability to induce polyclonal anti-tumor responses directed by the patient's immune system. EXPERIMENTAL DESIGN: Patients with unresectable MPM received two intrapleural doses of a replication-defective adenoviral vector containing the human interferon-alpha2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Bio-correlates on blood and tumor were measured. RESULTS: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n=7) or gemcitabine (n=15). Treatment was generally well tolerated. The overall response rate was 25% and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with non-epithelial histology. MOS in the first-line cohort was 12.5 months, while MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of interferon-alpha in blood or pleural fluid, induction of anti-tumor antibodies, nor an immune-gene signature in pretreatment biopsies. CONCLUSIONS: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. Overall survival rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone.

BACKGROUND: Malignant pleural effusion is a common complication of advanced malignancies. Indwelling tunneled pleural catheter (IPC) placement provides effective palliation but can be associated with complications, including infection. In particular, hematologic malignancy and the associated immunosuppressive treatment regimens may increase infectious complications. This study aimed to review outcomes in patients with hematologic malignancy undergoing IPC placement. METHODS: A retrospective multicenter study of IPCs placed in patients with hematologic malignancy from January 2009 to December 2013 was performed. Inclusion criteria were recurrent, symptomatic pleural effusion and an underlying diagnosis of hematologic malignancy. Records were reviewed for patient demographics, operative reports, and pathology, cytology, and microbiology reports. RESULTS: Ninety-one patients (mean +/- SD age, 65.4 +/- 15.4 years) were identified from eight institutions. The mean x SD in situ dwell time of all catheters was 89.9 +/- 127.1 days (total, 8,160 catheter-days). Seven infectious complications were identified, all of the pleural space. All patients were admitted to the hospital for treatment, with four requiring additional pleural procedures. Two patients died of septic shock related to pleural infection. CONCLUSIONS: We present, to our knowledge, the largest study examining clinical outcomes related to IPC placement in patients with hematologic malignancy. An overall 7.7% infection risk and 2.2% mortality were identified, similar to previously reported studies, despite the significant immunosuppression and pancytopenia often present in this population. IPC placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy.