Therapy For Malignant Mesothelioma Research Articles

Emerging insights into the biology and therapy of malignant mesothelioma

Malignant mesothelioma is an aggressive malignancy that may be caused by environmental carcinogens (asbestos and erionite), viruses (SV40), and genetic predisposition. Pleural malignant mesotheliomas are far more common than the peritoneal variants. Diagnosis relies on radiographic studies as well as histology and molecular biologic analyses. The prognostic scoring systems of the Cancer and Leukemia Group B and the European Organization for Research and Treatment of Cancer are the most useful of those currently available. These systems rate performance status, age, histology, and hematologic parameters as the best prognostic factors for mesothelioma. Most patients with mesothelioma are not candidates for surgical or radiotherapy treatment, and cytotoxic agents are the only options. Historically, no classes or combinations of agents consistently yielded response rates over 20%. Recently, pemetrexed has been evaluated in phase I, II, and III clinical trials with promising results. The phase II trial showed an overall response rate of 14.1% with a 1-year survival rate of 47.8%. A phase III trial of cisplatin versus cisplatin and pemetrexed closed in February 2002 and a final analysis was presented in May 2002. Novel targeted agents are also being tested in clinical trials among mesothelioma patients and include drugs inhibiting the vascular endothelial growth factor and its receptor, the epidermal growth factor receptor, and platelet-derived growth factor receptor. Semin Oncol 29 (suppl 18):35-42. Copyright 2002, Elsevier Science (USA). All rights reserved.

Emerging insights into the biology and therapy of malignant mesothelioma.

Malignant mesothelioma is an aggressive malignancy that may be caused by environmental carcinogens (asbestos and erionite), viruses (SV40), and genetic predisposition. Pleural malignant mesotheliomas are far more common than the peritoneal variants. Diagnosis relies on radiographic studies as well as histology and molecular biologic analyses. The prognostic scoring systems of the Cancer and Leukemia Group B and the European Organization for Research and Treatment of Cancer are the most useful of those currently available. These systems rate performance status, age, histology, and hematologic parameters as the best prognostic factors for mesothelioma. Most patients with mesothelioma are not candidates for surgical or radiotherapy treatment, and cytotoxic agents are the only options. Historically, no classes or combinations of agents consistently yielded response rates over 20%. Recently, pemetrexed has been evaluated in phase I, II, and III clinical trials with promising results. The phase II trial showed an overall response rate of 14.1% with a 1-year survival rate of 47.8%. A phase III trial of cisplatin versus cisplatin and pemetrexed closed in February 2002 and a final analysis was presented in May 2002. Novel targeted agents are also being tested in clinical trials among mesothelioma patients and include drugs inhibiting the vascular endothelial growth factor and its receptor, the epidermal growth factor receptor, and platelet-derived growth factor receptor.

Ifosfamide, mesna and interferon alfa combination therapy in malignant mesothelioma: results of a single center in central Anatolia, Turkey

Ifosfamide, mesna and interferon alfa combination therapy in malignant mesothelioma: results of a single center in central Anatolia, Turkey

Cytokine gene therapy of mesothelioma. Immune and antitumor effects of transfected interleukin-12.

Malignant mesothelioma (MM) is a solid tumor of the mesothelium for which there is no curative treatment. MM appears to be sensitive to immunotherapeutic approaches, and one of the most powerful immunomodulatory cytokines with antitumor effects is interleukin (IL)-12. We have previously shown in a murine model of MM that systemic administration of recombinant IL-12 induces a potent anti-MM immune response. The nature and accessibility of MM tumors means that they are suitable candidates for direct cytokine and gene-transfer therapeutic approaches. Therefore, we undertook a study to assess the antitumor effects induced by the local production of IL-12 within MM tumors by transfecting a murine MM line with the genes for IL-12. The IL-12 transfectant (AB1-IL-12) did not produce tumors in normal mice, but did so in athymic nude mice, implicating T cells in the prevention of MM tumor growth. In mixing experiments, paracrine IL-12 production inhibited growth of untransfected MM cells provided that cells producing IL-12 represented more than 50-80% of the inoculum. Furthermore, BALB/c mice previously challenged with AB1-IL-12 were protected against rechallenge with parental AB1 tumor, indicating that the transfectant induced long-term immunity. AB1-IL-12 induced systemic immunity that was effective at reducing the incidence of parental AB1 tumor at a distal site, but its effects were dose-dependent. Though both CD4(+) and CD8(+) cells infiltrated the rejecting tumor, CD8(+) effector cells were essential for protection against development of parental AB1 tumor. This study shows that paracrine secretion of IL-12, generated by gene transfer, can induce immunity against MM that can act locally and also at a distant site. In addition, there was no evidence of toxicity, which has been associated with the systemic administration of IL-12, indicating that this cytokine is a good candidate for experimental gene therapy in MM.

A phase II study of gemcitabine in patients with malignant pleural mesothelioma

BACKGROUND Gemcitabine has shown activity in patients with less chemosensitive solid tumors. Phase II screening of novel drugs is an accepted method with which to investigate new therapies in malignant mesothelioma. The European Organization for Research and Treatment of Cancer-Lung Cancer Cooperative Group has performed several sequential Phase II trials of new agents for the treatment of mesothelioma over the last 10 years. METHODS Twenty-seven chemotherapy-naive patients with histologically proven malignant mesothelioma were treated with gemcitabine as a 30-minute intravenous administration of 1250 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Therapy continued for up to ten cycles unless disease progression or excessive toxicity mandated discontinuation. RESULTS With a median relative dose intensity of 96%, toxicity was mild and neutropenia of ≥ Grade 3 (according to National Cancer Institute criteria) occurred in 30% of patients, without episodes of febrile neutropenia. One case of hemolytic-uremic syndrome, most likely related to gemcitabine use, was observed. Overall, 2 objective responses were observed (response rate of 7%; 95% confidence interval, 1-24%). The median survival was 8 months. CONCLUSIONS At the prescribed dosage and schedule, single agent gemcitabine appears to have limited activity in chemotherapy-naive patients with malignant pleural mesothelioma. Cancer 1999;85:2577–82. © 1999 American Cancer Society.

Adenovirus-mediated gene therapy for malignant mesothelioma: A comparison of immunosuppressed, immunodeficient and immunocompetent tumor models

Adenovirus-mediated gene therapy for malignant mesothelioma: A comparison of immunosuppressed, immunodeficient and immunocompetent tumor models

The role of growth factors and cytokines in the tumorigenesis and immunobiology of malignant mesothelioma.

Malignant mesothelioma (MM) is an asbestos-associated cancer that is increasing in incidence worldwide and is refractory to conventional therapy. MM cells are potent sources of a number of cytokines, some of which have recently been shown to be directly involved in the aggressive growth and spread of MM tumors. Emerging data also suggest involvement of MM-derived cytokines in systemic paraneoplastic syndromes including immunosuppression, thrombocytosis, cachexia, amyloidosis, and hypoglycemia. Additional characterization of the expression of cytokines and cytokine receptors in situ in MM tumors may provide a more complete picture of the autocrine and paracrine processes which occur in MM. Improved therapy of MM, particularly cytokine-based approaches, is likely to benefit from further elucidation of the patterns and regulation of cytokine expression associated with MM tumors.

Potential for cytokine therapy of malignant mesothelioma

*Transplantation Biology Unit, K Floor, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4029, Australia; tCell Biology Research Unit, Z Block Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia, #Department of Respiratory Medicine, B Block, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia SDepartment of Medicine, University of Western Australia, G Block, Queen Elizabeth II Medical Centre, Nedlands, Western Australia 6009, Australia, and $?School of Life Science, Queensland University of Technology, Brisbane, Queensland 4001, Australia.

Immunocytochemical characterization of cell lines from human malignant mesothelioma: Characterization of human mesothelloma cell lines by immunocytochemistry with a panel of monoclonal antibodies

A panel of nine monoclonal antibodies was used to characterize human mesothelioma cell lines that we established from human malignant mesothelioma. The antigens detected were cytokeratin, vimentin, epithelial membrane antigen, carcinoembryonic antigen, Leu-M1 (CD15), desmin, factor VIII-related antigen (von Willebrand factor antigen), OV632, and ME1, a specific monoclonal antibody directed against human malignant mesothelioma. The technique used was the alkaline phosphatase anti-alkaline phosphatase method. All 30 cell lines, either epithelial, sarcomatous, or mixed, showed strong reactivity with cytokeratin and vimentin antibodies. None of the cell lines demonstrated any reactivity with carcinoembryonic antigen, Leu-M1, or factor VIII antibodies; moreover, all of 22 cell lines studied were positive for ME1 antibody and 10 of 12 cell lines studied were positive for OV632. Some interesting features were noted: only two of the 30 cell lines presented a weak positive staining with epithelial membrane antigen, and nine of 19 cell lines tested demonstrated a cytoplasmic staining pattern with desmin antibody. These results show that established human mesothelioma cell lines still possess the immunocytochemical characteristics that are basically consistent with the immunohistochemical features described in tumor tissues of malignant mesothelioma. These characteristics can be used to identify the mesothelioma cells grown from human malignant mesothelioma. Hence, the mesothelioma cell lines will provide a useful tool for the investigation of the cell biology of the tumor and the mechanisms of mesothelial cell transformation, as well as the in vitro evaluation of the effects of some drugs in order to develop new therapies for malignant mesothelioma.

Usefulness of the nude mouse model in mesothelioma based on a direct patient–xenograft comparison

A patient with malignant mesothelioma experienced tumor recurrence 3 months after pleuropneumonectomy. Samples of the tumor were transplanted into nude mice to assess chemosensitivity. There was close concordance between the results in xenografts and the clinical outcome in this patient. Both mitomycin and to a lesser extent cisplatin were effective as single agents against the nude mouse xenografts, and the combination of these two drugs produced a complete response both in the patient and in the xenografts. The patient survived 18 months from onset of chemotherapy and 24 months from diagnosis. The duration of clinical complete response to chemotherapy was 14 months, despite the fact that mitomycin, the most effective agent against the xenografts, was discontinued after only two cycles because the patient developed pulmonary toxicity. This direct patient-xenograft correlation further validates the usefulness of the nude mouse model in the search for effective therapies for malignant mesothelioma, a tumor characterized by frequent refractoriness to most available agents.