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1.  Malignant Pleural Mesothelioma: Update on Treatment Options with a Focus on Novel Therapies 
Clinics in chest medicine  2013;34(1):99-111.
doi:10.1016/j.ccm.2012.12.005
PMCID: PMC3612173  PMID: 23411061
malignant pleural mesothelioma; radiation therapy; chemotherapy; multimodal therapy; gene therapy
2.  A Live-attenuated Listeria Vaccine (ANZ-100) and a Live-attenuated Listeria Vaccine Expressing Mesothelin (CRS-207) for Advanced Cancers: Phase 1 Studies of Safety and Immune Induction 
Clinical Cancer Research  2011;18(3):858-868.
Purpose
Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses, and activation and recruitment of NK and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T cell responses against mesothelin-expressing murine tumors. These two Phase 1 studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively.
Experimental Design
A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1×106, 3×107, or 3×108 colony forming units [cfu]. CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic or ovarian cancers. 17 subjects received up to 4 doses of 1×108, 3×108, 1×109, or 1×1010 cfu.
Results
A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1×109 cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, Listeriolysin O and mesothelin-specific T cell responses were detected and 37% of subjects lived ≥ 15 months.
Conclusions
ANZ-100 and CRS-207 administration was safe and resulted in immune activation.
doi:10.1158/1078-0432.CCR-11-2121
PMCID: PMC3289408  PMID: 22147941
Listeria; Cancer Vaccines; Mesothelin; Immunotherapy; Phase 1
3.  A Trial of Intrapleural Adenoviral-mediated Interferon-α2b Gene Transfer for Malignant Pleural Mesothelioma 
New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe “flu-like” symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor.
Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).
doi:10.1164/rccm.201103-0554CR
PMCID: PMC3262033  PMID: 21642245
clinical trials; immunotherapy; gene therapy
4.  GENE THERAPY FOR LUNG NEOPLASMS 
Clinics in chest medicine  2011;32(4):865-885.
SYNOPSIS
Both advanced stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Although there have been advances in treatment regimens for both diseases, these have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.
doi:10.1016/j.ccm.2011.08.006
PMCID: PMC3210443  PMID: 22054892
Gene Therapy; Immunotherapy; Lung cancer; Mesothelioma
5.  Photodynamic therapy for the treatment of non-small cell lung cancer 
Journal of Thoracic Disease  2012;4(1):63-75.
Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described.
doi:10.3978/j.issn.2072-1439.2011.11.05
PMCID: PMC3256541  PMID: 22295169
Photodynamic therapy; lung cancer; endobronchial; palliative care; non-small cell lung cancer
6.  Advances in Diagnostic Bronchoscopy 
Diagnostic bronchoscopy has undergone two major paradigm shifts in the last 40 years. First, the advent of flexible bronchoscopy gave chest physicians improved access to the tracheobronchial tree with a rapid learning curve and greater patient comfort compared with rigid bronchoscopy. The second paradigm shift has evolved over the last 5 years with the proliferation of new technologies that have significantly enhanced the diagnostic capabilities of flexible bronchoscopy compared with traditional methods. At the forefront of these new technologies is endobronchial ultrasound. In its various forms, endobronchial ultrasound has improved diagnostic yield for pulmonary masses, nodules, intrathoracic adenopathy, and disease extent, thereby reducing the need for more invasive surgical interventions. Various navigational bronchoscopy systems have become available to increase flexible bronchoscope access to small peripheral pulmonary lesions. Furthermore, various modalities of airway assessment, including optical microscopic imaging technologies, may play significant roles in the diagnosis of a variety of pulmonary diseases in the future. Finally, the combination of new diagnostic bronchoscopy technologies and novel approaches in molecular analysis and biomarker assessment hold promise for enhanced diagnosis and personalized management of many pulmonary disorders. In this review, we provide a contemporary review of diagnostic bronchoscopy developments over the past decade.
doi:10.1164/rccm.201002-0186CI
PMCID: PMC3159074  PMID: 20378726
endobronchial ultrasound; lung cancer; autofluorescence; tomography; confocal
7.  Evaluation of an Attenuated Vesicular Stomatitis Virus Vector Expressing Interferon-β for Use in Malignant Pleural Mesothelioma: Heterogeneity in Interferon Responsiveness Defines Potential Efficacy 
Human Gene Therapy  2009;21(1):51-64.
Abstract
Vesicular stomatitis virus (VSV) has shown promise as an oncolytic agent, although unmodified VSV can be neurotoxic. To avoid toxicity, a vector was created by introducing the interferon-β (IFN-β) gene (VSV.IFN-β). We conducted this study to determine the ability of VSV.IFN-β to lyse human cancer (mesothelioma) cells and to evaluate the potential of this recombinant virus for clinical translation. Four normal human mesothelial and 12 mesothelioma cell lines were tested for their susceptibility to VSV vectors in vitro. VSV.hIFN-β did not cause cytotoxicity in any normal lines. Only 4 of 12 lines were effectively lysed by VSV.hIFN-β. In the eight resistant lines, pretreatment with IFN-β prevented lysis of cells by VSV.GFP, and VSV infection or addition of IFN-β protein resulted in the upregulation of double-stranded RNA-dependent protein kinase (PKR), myxovirus resistance A (MxA), and 2′,5′-oligo-adenylate-synthetase (2′5′-OAS) mRNA. In the susceptible lines, there was no protection by pretreatment with IFN-β protein and no IFN- or VSV-induced changes in PKR, MxA, and 2′5′-OAS mRNA. This complete lack of IFN responsiveness could be explained by marked downregulation of interferon alpha receptors (IFNARs), p48, and PKR in both the mesothelioma cell lines and primary tumor biopsies screened. Presence of p48 in three tumor samples predicted responsiveness to IFN. Our data indicate that many mesothelioma tumors have partially intact IFN pathways that may affect the efficacy of oncolytic virotherapy. However, it may be feasible to prescreen individual susceptibility to VSV.IFN-β by immunostaining for the presence of p48 protein.
doi:10.1089/hum.2009.088
PMCID: PMC2829454  PMID: 19715403

Results 1-7 (7)