Faculty Bibliography

Immunotherapy against a variety of malignancies, including pleural-based malignancies, has shown promise in animal models and early human clinical trials, but successful efforts will need to address immunosuppressive factors of the tumor and host, particularly certain cytokines and CD4(+) CD25(+) regulatory T cells (Treg). Here, we evaluated the cellular and cytokine components of malignant pleural effusions from 44 patients with previously diagnosed mesothelioma, non-small cell lung cancer (NSCLC), or breast cancer and found significant differences in the immune profile of pleural effusions secondary to mesothelioma vs. carcinoma. Although a high prevalence of functionally suppressive CD4(+) CD25(+) T cells was found in carcinomatous pleural effusions, mesothelioma pleural effusions contained significantly fewer CD4(+) CD25(+) T cells. Activated CD8(+) T cells in pleural fluid were significantly more prevalent in mesothelioma than carcinoma. However, there is clear patient-to-patient variability and occasional mesothelioma patients with high percentages of CD4(+) CD25(+) pleural effusion T cells and low percentages of CD8(+) CD25(+) pleural effusion T cells can be identified. Mesothelioma pleural effusions contained the highest concentrations of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Thus, the contribution of cellular and cytokine components of immunosuppression associated with malignant pleural effusions varies by tumor histology and by the individual patient. These results have implications for the development of immunotherapy directed to the malignant pleural space, and suggest the need to tailor immunotherapy to overcome immunosuppressive mechanisms in tumor environments.

BACKGROUND: Malignant pleural effusions (MPEs) can produce significant respiratory symptoms and diminished quality of life in patients with terminal malignancies. Control of MPEs to palliate respiratory symptoms can be performed via several different approaches. Ideally, a minimally invasive procedure to control MPEs and to provide relief of respiratory symptoms would be optimal. OBJECTIVE: To ascertain if control of MPEs can be achieved by outpatient management via a small-bore pleural catheter (PC) without the need for sclerosing agents. METHODS: Retrospective chart analysis of 24 patients after outpatient insertion of PCs for recurrent, symptomatic MPEs followed by frequent home drainage of pleural fluid to relieve respiratory symptoms. RESULTS: Symptomatic relief of respiratory symptoms was achieved in 100% of patients, while pleurodesis was achieved in 58% of patients in a mean of 39 days. Five patients (6 PCs) expired with the catheters in place. In these patients, all catheters remained in position and functional until the patients ultimately died from nonpleural disease progression. No major complications occurred during insertion of the catheter. Late complications included localized cellulitis and bacterial superinfection in three patients and tumor growth at the catheter site in one patient. CONCLUSIONS: The PCs used in the present study provided an effective modality not only to alleviate respiratory symptoms associated with MPE, but also to achieve pleurodesis in 58% of our patients. These catheters may provide a significantly less invasive outpatient approach to the palliative management of MPEs.

Gene therapy for pulmonary disease, a field still in the experimental stage, has nonetheless progressed considerably in the past decade. There have been significant advances in pre-clinical studies, as well as important developments resulting from multiple early-phase human clinical trials for a variety of respiratory disorders. Although there are several ways of delivering therapeutic genes to the lungs, the primary delivery modality remains flexible bronchoscopy. The flexible bronchoscope, because of its unique access to both large and small airways, serves as an ideal instrument to deliver therapeutic genes to the tracheobronchial tree, even to small airways and alveoli that are beyond the reach of the bronchoscope. In addition, bronchoscopic gene delivery has the capacity to treat pulmonary vascular disorders because delivery of marker and therapeutic genes via the airways has been demonstrated to successfully transduce the pulmonary vascular endothelium. This article describes the various methods and disease targets of bronchoscopically mediated gene therapy, focusing in particular on the results of clinical studies and providing a glimpse into the future of the field.

To evaluate the feasibility, safety, and efficacy of vaccination with autologous tumor cells genetically modified with an adenoviral vector (Ad-GM) to secrete human granulocyte-macrophage colony-stimulating factor (GM-CSF), we conducted a phase I/II multicenter trial in patients with early and advanced stage non-small-cell lung cancer (NSCLC). Vaccines were generated from autologous tumor harvests. Intradermal injections were given every 2 weeks for a total of three to six vaccinations. Tumors were harvested from 83 patients, 20 with early-stage NSCLC and 63 with advanced- stage NSCLC; vaccines were successfully manufactured for 67 patients, and 43 patients were vaccinated. The most common toxicity was a local injection-site reaction (93%). Three of 33 advanced-stage patients, two with bronchioloalveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and >or=22 months). Longer survival was observed in patients receiving vaccines secreting GM-CSF at more than 40 ng/24 h per 10(6) cells (median survival = 17 months, 95% confidence interval [CI] = 6 to 23 months) than in patients receiving vaccines secreting less GM-CSF (median survival = 7 months, 95% CI = 4 to 10 months) (P =.028), suggesting a vaccine dose-related survival advantage.

OBJECTIVES: Immuno-gene therapy of mesothelioma with an adenovirus encoding interferon-beta mediated strong antitumor responses in murine models with low but not high tumor burden. Our goals were to determine the mechanisms responsible for this loss of efficacy and to test the hypothesis that the combination of preoperative adenovirus encoding interferon-beta and surgical resection would be effective in treating bulky tumors. METHODS: Flank tumors of a mouse mesothelioma cell line were treated with adenovirus encoding interferon-beta or adenoviral vector encoding the bacterial protein beta-galactosidase. Cytotoxic T lymphocytes and tumor infiltration by T lymphocytes were measured. Tumors were surgically excised 72 hours later and tumor cells were injected in the contralateral flank to create a model of a metastatic focus. Tumor-free survival and distant metastatic disease were assessed. RESULTS: Immuno-gene therapy effectively treated small tumors (<200 mm(3)) but did not reduce the size of large (>800 mm(3)) flank tumors. Although treatment with adenovirus encoding interferon-beta resulted in the generation of tumor-neutralizing splenocytes in large tumors, the number of T cells visualized within the tumors was minimal. Tumors treated with adenovirus encoding interferon-beta (versus adenoviral vector encoding the bacterial protein beta-galactosidase or phosphate-buffered saline solution) prior to debulking increased long-term tumor-free survival and resulted in two- to sixfold smaller foci of implanted tumor cells at 2 weeks postoperatively. CONCLUSIONS: The use of adenovirus encoding interferon-beta or surgical debulking alone is ineffective in treating large tumors, but combining preoperative adenovirus encoding interferon-beta and surgical debulking significantly reduces tumor recurrence and improves long-term tumor-free survival. We postulate that adenovirus encoding interferon-beta amplifies the cytotoxic T-lymphocyte antitumor response, allowing elimination of residual tumor cells.

Nonanastomotic bronchial stenosis is a rare complication of lung transplantation. We report a case of a bilateral lung transplant recipient who experienced recalcitrant stenosis of the bronchus intermedius. All attempts at conservative management failed, and the stricture was successfully treated by a parenchymal-sparing segmental sleeve resection. Although rare, this is an important technique in the management of this difficult problem.

Surgical debulking of malignant mesothelioma (MM) ultimately fails due to local recurrence. Suramin, an inhibitor of extracellular growth factors (ECGFs), has demonstrated efficacy in the treatment of malignant mesothelioma in a small case series. Our goal was to study survival benefits and disease progression in several MM animal models treated with suramin as a potential agent for adjuvant therapy. In vitro growth of human (REN, I-45), rat (II-45) and murine (AB12) mesothelioma cell lines were measured with or without suramin exposure. Human and murine MM tumors were implanted subcutaneously into murine flanks or injected intraperitoneally (i.p.) into murine abdominal cavities. Dose and treatment schedules were optimized to reduce the rate of tumor progression and to improve survival curves. Suramin inhibited the in vitro growth of all cell lines, reaching statistical significance (P<0.01) three doubling cycles after suramin administration, with a maximum inhibition of 10-25% of control growth. A significant time- and dose-dependent effect was observed. In vivo, suramin inhibited the growth of MM in the xenogeneic model (55% of control growth, P<0.01), and in the syngeneic model at both the low and high loading doses (46 and 36% of control growth, respectively, P<0.01). Suramin treatment inhibited in vivo growth in the REN intraperitoneal model shown grossly by necropsy of same day deaths comparing treatment and control animals. Tumor inhibition with the higher dose was also reflected by the lower mean tumor burden scores (control: 4.0 and high dose: 3.4). Suramin inhibits the growth of human, murine, and rat MM in vitro, in a time- and dose-dependent manner. Suramin also inhibits the growth of human MM flank and intraperitoneal xenografts in vivo in an immunodeficient host, as well as the growth of syngeneic murine flank tumors in an immunocompetent host. These studies demonstrate that suramin may have the potential to provide effective therapy for MM, and that further studies are necessary to elucidate the survival advantage of suramin mediated MM growth inhibition.

Antitumor effects of cyclooxygenase-2 (COX-2) inhibition have been reported in a wide variety of tumor models and in human cancers, both as chemoprevention and therapy. Human mesothelioma tumors have been shown to overexpress COX-2 and high levels of COX-2 protein have been demonstrated to be a prognostic factor, indicating poor outcome in this tumor. In this study, we determined that inhibition of COX-2 by oral administration of Rofecoxib significantly slowed but did not cure the growth of small tumors in mesothelioma-bearing mice. Large tumors were unaffected. This effect was dependent on the presence of CD8+ T cells and was associated with increased tumor-infiltrating lymphocytes. Because these activities are consistent with a mechanism that results in a decrease in the immunosuppressive environment of the tumor, we additionally examined the effect of COX-2 blockade combined with Ad.IFN-beta therapy, a treatment that we have previously demonstrated results in expansion of antitumor CD8+ CTLs and cures a high percentage of small mesothelioma tumors in mice. Ad.IFN-beta therapy combined with COX-2 inhibition was associated with an increased number of T cells within tumors and resulted in cures of small tumors, significant inhibition of the growth of large established tumors, and inhibition of the growth of metastatic tumor foci after surgical debulking. The additive effects of these modes of treatment suggests that it would be rational to combine COX-2 inhibition with immuno- and immunogene therapy approaches (perhaps in conjunction with surgical debulking) in human clinical trials of treatment of mesothelioma and other tumors.