Faculty Bibliography

Background A 47-year-old woman with a history of ovarian cancer and a 6-year disease-free remission presented with dyspnea and increased abdominal girth. The patient was found to have ascites and a large left pleural effusion, both of which contained malignant cells consistent with recurrent ovarian cancer. Her disease progressed despite treatment with chemotherapeutic and hormonal agents. She was then enrolled in a phase I clinical trial of adenoviral-mediated interferon beta gene therapy. Investigations Abdominal and chest CT scans, 2-[(18)F]fluoro-2-deoxyglucose PET scan, viral cultures, interferon cytokine analysis, immunophenotyping, and tumor cytotoxicity analyses. Diagnosis Stage IV ovarian cancer with malignant ascites and pleural effusion. Management Tunneled pleural catheter and intrapleural adenoviral-mediated interferon beta gene therapy.

Tumor vaccines composed of autologous tumor cells genetically modified to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) (GVAX) have demonstrated clinical activity in advanced-stage non-small-cell lung cancer (NSCLC). In an effort to remove the requirement for genetic transduction of individual tumors, we developed a 'bystander' GVAX platform composed of autologous tumor cells mixed with an allogeneic GM-CSF-secreting cell line. We conducted a phase I/II trial of this vaccine (3-12 biweekly vaccinations) in advanced-stage NSCLC. Tumors were harvested from 86 patients, tumor cell processing was successful in 76, and 49 proceeded to vaccination. The most common toxicity was local vaccine injection site reactions. Serum GM-CSF pharmacokinetics were consistent with secretion of GM-CSF from vaccine cells for up to 4 days with associated transient leukocytosis confirming the bioactivity of vaccine-secreted GM-CSF. Evidence of vaccine-induced immune activation was demonstrated; however, objective tumor responses were not seen. Compared with autologous GVAX vaccines prepared by transduction of individual tumors with an adenoviral GM-CSF vector, vaccine GM-CSF secretion was approximately 25-fold higher with the bystander GVAX vaccine used in this trial. However, the frequency of vaccine site reactions, tumor response, time to disease progression, and survival were all less favorable in the current study.

Adenoviral immuno-gene therapy using interferon-beta has been effective in an orthotopic model of lung cancer. However, pulmonary inflammation induced by adenoviral (Ad) vectors will almost certainly limit the maximally tolerated dose. On the other hand, the strong innate immune response generated by the vector may be helpful in initiating the adaptive immune response required for efficacy. The goals of this study were to develop an effective approach to inhibit Ad.IFNbeta-mediated acute pulmonary inflammation and to determine whether this reduction of Ad-mediated inflammation decreased the therapeutic efficacy of Ad.IFNbeta in a mouse model of bronchioloalveolar cancer. Our data show that anti-TNF-alpha antibodies can blunt the innate pulmonary immune response induced by Ad vectors, even in sensitized animals. However, this effect also inhibited the ability of the animal to generate anti-tumor immune responses and reduced survival in an orthotopic lung cancer model responsive to Ad.IFNbeta treatment. Interestingly, in a flank model of tumor using a cell line derived from the lung tumor, TNF-alpha blockade did not inhibit efficacy. These data suggest that the innate immune response to adenovirus in the lung may be important in immuno-gene therapy of lung cancer. Therapeutic application of anti-inflammatory therapy in immuno-gene therapy strategies should thus be undertaken with caution.

BACKGROUND AND OBJECTIVE: Transbronchial needle catheters are commonly used during flexible and rigid bronchoscopy for needle aspiration. The use of these catheters can be expanded by employing the technique of transbronchial needle injection. METHODS AND RESULTS: By injecting lesions in the airways, peribronchial structures, mediastinum, or lung parenchyma, transbronchial needle injection has been applied to the treatment of lung cancer, inflammatory disorders of the airways, recurrent respiratory papillomatosis, as well as bronchopleural fistulas. Diagnostic applications have included the localization of peripheral lung nodules as well as sentinel lymph nodes. CONCLUSIONS: Our review defines this bronchoscopic technique and summarizes its various reported applications.

Gene therapy for mesothelioma is currently in its adolescence. The expansion of knowledge regarding molecular aspects of mesothelioma carcinogenesis has facilitated the development of promising gene therapy modalities that target specific oncoproteins and mutant tumor suppressor genes. Although implementation of any of these gene therapy approaches as part of standard medical care for patients who have mesothelioma remains years in the future, the field is finally progressing toward more definitive phase II/III efficacy studies. Unfortunately, the marginal benefits garnered from standard anticancer treatments in mesothelioma argue strongly for continued participation in clinical studies of various experimental approaches, particularly gene therapy. These trials serve multiple purposes: to establish safety, determine proper dosing, evaluate for efficacy, and, in an iterative fashion, guide future avenues of laboratory investigation.

PURPOSE: Delineation of the long-term follow-up data on a series of patients with malignant mesothelioma, who received a single intrapleural dose of a nonreplicative adenoviral (Ad) vector encoding the herpes simplex virus thymidine kinase "suicide gene" (Ad.HSVtk) in combination with systemic ganciclovir. EXPERIMENTAL DESIGN: This report focuses on the 21 patients receiving "high-dose" therapy, defined by an intrapleural dose of vector (> or =1.6 x 10(13) viral particles), where transgene-encoded tk protein was reliably identified on immunohistochemical staining. In 13 patients, the vector was deleted in the E1 and E3 regions of the Ad; in the other eight patients, the vector had deletions in the Ad genes E1 and E4. Safety, immunologic responses, transgene expression, and clinical responses were evaluated. RESULTS: Both the E1/E3-deleted vector and the E1/E4-deleted vector were well tolerated and safe, although production of the E1/E4 vector was more difficult. Posttreatment antibody responses against the tumors were consistently seen. Interestingly, we observed a number of clinical responses in our patients, including two long-term (>6.5 year) survivors, both of whom were treated with the E1/E4-deleted vector. CONCLUSIONS: Intrapleural Ad.HSVtk/ganciclovir is safe and well tolerated in mesothelioma patients and resulted in long-term durable responses in two patients. Given the limited amount of gene transfer observed, we postulate that Ad.HSVtk may have been effective due to induction of antitumor immune responses. We hypothesize that approaches aiming to augment the immune effects of Ad gene transfer (i.e., with the use of cytokines) may lead to increased numbers of therapeutic responses in otherwise untreatable pleural malignancies.

Tumors of the mediastinum represent a wide diversity of disease states. The location and composition of a mass is critical to narrowing the differential diagnosis. The most common causes of an anterior mediastinal mass include the following: thymoma; teratoma; thyroid disease; and lymphoma. Masses of the middle mediastinum are typically congenital cysts, including foregut and pericardial cysts, while those that arise in the posterior mediastinum are often neurogenic tumors. The clinical sequelae of mediastinal masses can range from being asymptomatic to producing symptoms of cough, chest pain, and dyspnea. This article will review the anatomy of the mediastinum as well as the different clinical, radiographic, and prognostic features, and therapeutic options of the most commonly encountered masses.

Given previous work showing that an adenoviral vector expressing IFN-beta (Ad.IFNbeta) was highly effective in eradicating i.p. mesothelioma tumors, the antitumor efficacy of this agent was evaluated in an orthotopic model of bronchogenic adenocarcinoma of the lung. These transgenic mice have a conditionally expressed, oncogenic K-rasG12D allele that can be activated by intratracheal administration of an adenovirus expressing Cre recombinase (Ad.Cre). K-rasG12D mutant mice were given Ad.Cre intranasally to activate the oncogene. Mice were then given 10(9) plaque-forming units of a control vector (Ad.LacZ) or Ad.IFNbeta intranasally 3 and 4 weeks later, a time when lung tumors had been established. Cells derived from K-ras-mutated lung tumors were also grown in the flanks of mice to study mechanisms of therapeutic responses. In two separate experiments, untreated tumor-bearing mice all died by day 57 (median survival, 49 days). Ad.LacZ-treated mice all died by day 71 (median survival, 65 days). In contrast, 90% to 100% of mice treated with Ad.IFNbeta were long-term survivors (>120 days; P < 0.001). In addition, immunity to re-challenge with tumor cells was induced. In vitro and flank tumor studies showed that Ad.IFNbeta induced direct tumor cell killing and that depleting natural killer or CD8+ T cells, but not CD4+ T cells, with antibodies attenuated the effect of Ad.IFNbeta. These studies, showing remarkable antitumor activity in this orthotopic lung cancer model, provide strong preclinical support for a trial of Ad.IFNbeta to treat human non-small cell lung cancer.

Malignant mesothelioma is an insidious neoplasm arising from the mesothelial surfaces of the pleural and peritoneal cavities, the pericardium, or the tunica vaginalis. A total of 80% of all cases are pleural in origin. The predominant cause of malignant mesothelioma is inhalational exposure to asbestos, although evidence is increasing to support the hypothesis that simian virus-40 virus plays a role in cocarcinogenesis. Immunohistochemical markers such as calretinin, WT-1, and cytokeratin 5/6 are becoming established diagnostic markers. Preliminary data suggests that a soluble form of mesothelin could serve as a serum marker for established and early cases of mesothelioma. Positron emission tomography with 18-fluorodeoxyglucose in conjunction with computed tomograhy scanning has improved preoperative imaging and staging. Prognostic factors have been identified and verified. Negative indicators include thrombocytosis, high leukocyte counts, poor performance status, and nonepithelial histology. For the first time, there is now evidence that some treatments are increasing the quality and quantity of life for patients with mesothelioma. Chemotherapy, with the new multi-targeted antifolate drug Pemetrexed, combined with cisplatin, has shown superior survival rates in a large phase III trial when compared to cisplatin alone. High-dose intensity-modulated radiotherapy when administered after extrapleural pneumonectomy has resulted in excellent local control. Multimodality treatment programs that combine surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of mesothelioma patients. Innovative palliative approaches have proved successful in alleviation of the significant symptoms experienced by many mesothelioma patients. Experimental treatments such as immunotherapy and gene therapy present a window of hope for all mesothelioma patients, and in the future, may be combined with 'standard therapy' in multimodality protocols. Patients with adequate performance status should be enrolled into clinical trials where possible. Over the past decade, significant advances have been made on several fronts that have improved the ability to diagnose a stage, define prognosis, and treat malignant pleural mesothelioma.