Article by: Masatoshi Tagawa (A) & (B), Yuji Tada (C), Kenzo Hiroshima (D) and Hideaki Shimada (E)
Mesothelioma is relatively rare in frequency but is one of the intractable cancers linked with asbestos exposure. The patient numbers will increase in near future and current clinical outcomes with conventional treatment modalities are not satisfactory. Gene therapy is a possible therapeutic strategy because of easy accessibility of a vector system into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced anti-tumor effects, suggesting the clinical feasibility. In this review, we summarized the current status of clinical trials targeting mesothelioma.
Malignant pleural mesothelioma
Malignant pleural mesothelioma is a solid tumor developed in the thoracic cavity and extends into the vicinity organs to disturb the functions of vital organs such as lungs, large vessels and heart, which results in respiratory failure, cardiac tamponade and even spinal cord compression. These symptoms damage the patient’s quality of life. Development of malignant pleural mesothelioma has been closely associated with asbestos exposure in most of the cases and the latent period is extremely long beyond 30 years. Asbestos usage is inhibited in most of the Western countries but is being utilized in economically emerging countries. Statistical analyses based on asbestos consumption and the average latent periods imply that the incidence has reached its peak or will be maximal within next two decades in the major Western societies (1) and perhaps we will have more patients in the emerging areas. No effective prevention method is currently developed, which prompt us seek for novel treatment approaches.
The prognosis of malignant pleural mesothelioma is poor with 6-9 months of the median survival time after the diagnosis. Conventional therapies for malignant pleural mesothelioma consist of surgery and chemotherapy. Extrapleural pneumonectomy, resection of pleura with lung, can be curative in the early stage but the eligible patient numbers are limited and majority of the patients results in local recurrence with no further effective treatments. malignant pleural mesotheliomacells are resistant to radiation and in fact clinical responses to radiotherapy proved to be disappointing. Malignant pleural mesothelioma cells are also resistant to chemotherapeutic agents and many clinical trials even in a combination of agents have failed to prolong the overall survival. Recently, pemetrexed, a multi-targeted anti-folate agent, has extended the survival period from 9.3 months with cisplatin treatment alone to 12.1 months in combination with cisplatin (2). The clinical outcome even with the updated combination chemotherapy is thus not satisfactory. A combination of three treatment modalities, surgery followed by chemotherapy and radiotherapy, are now being investigated for the clinical benefits. Nonetheless, the patients are old and suffered from chronic respiratory failure after a long-term asbestos exposure and thereby a novel treatment is needed to favor the quality of patient life.
Clinical studies for Malignant Pleural Mesothelioma
Two major phase I studies have been conducted in USA with replication-incompetent type 5 adenoviruses (Ad) expressing a herpes simplex virus thymidine kinase (HSVtk) gene (Ad-HSVtk) (3) or interferon (IFN)-b gene (Ad-IFN-b) (4). HSVtk-positive allogeneic cells (5) and vaccinia viruses expressing the interleukin-2 (IL-2) gene were also tested in a phase I and a pilot study, respectively. The study with Ad-HSVtk is a representative suicide gene therapy, in which anti-viral prodrug ganciclovir (GCV) is used in the combination. GCV is phosphorylated by HSVtk but not by the mammalian tk and phosphorylated/diphosphorylated GCV are incorporated into DNA to terminate DNA synthesis. Expression of HSVtk followed by GCV administration thus produces cytotoxic effects to the mammalian cells expressing the gene.
A phase I clinical trial with Ad-HSVtk and subsequent GCV administration was conducted at the University of Pennsylvania, which enrolled 34 patients without prior chemotherapy (Table). Patients received single intrapleural injection of Ad-HSVtk and the dose escalation study showed that the patients tolerated well to high Ad doses. The study demonstrated that the gene therapy was safe with minimal adverse reactions and successful gene transfer into the tumors was observed in 17 of 25 evaluable patients. It is difficult to assess the clinical outcomes in a phase I study but the study showed 3 cases survived more than 5 years, which is extraordinary good in the prognosis of MPM patients. All the long-lived cases were in an early stage of the disease but 2 patients did not receive any other treatments besides the gene therapy. The clinical investigators showed that immune responses were generated in the patients and implied that immune responses played a crucial role in the anti-tumor responses. Repeated administrations of Ad-HSVtk induced humoral and cell-mediated immunity against the Ad but the humoral immunity did not deteriorate the efficacy of gene transfer nor induced serious adverse effects. Generation of anti-Ad antibody might be rather beneficial to prevent systemic distribution of Ad. Gene-modified ovarian cancer cells expressing HSVtk was administered into the intrapleural cavity of malignant pleural mesothelioma patients in a phase I trial (5). The clinical trial showed that the cell-based gene therapy was safe and the cells successfully homed to adhere to the malignant pleural mesothelioma lining the thoracic cavity. The clinical benefits were however not well demonstrated.
Table: Clinical trials with viral vectors for malignant pleural mesothelioma
Vector Doses
(Reference)
Transgene
Expressed
Patient
Numbers
Clinical Outcomes
(I) Phase I with Ad
5x1010 - 5x1012 vp*HSVtk13PD: 12 patients
(3)Long lived (>113.5 mo): 1
1.5x1013 - 5x1013 vp21PD:19
(3)Long lived (>79.5 mo): 2
(II) Phase I with Ad
9x1011 - 3x1012 vpIFN-b8SD: 3, PD: 5 (by CT on day 60)
(4)Immunological response: 2
(III) Phase I Ad
1x108 – 1x1010 cellsHSVtk-expressing allogeneic cells16No data
(adherent to MPM lining the chest)
(IV) Pilot study with Vaccinia
unknownIL-26No response
Table Legend: Progressive disease (PD) and stable disease (SD) are judged by the measurable tumor sizes. *vp: virus particle
Malignant pleural mesothelioma is a typical non-immunogenic tumor and often produces immunosuppressive cytokines, inducing tolerance of host immunity. In order to up-regulate the immunity, two clinical trials of the immunology-based gene therapy with vaccinia viruses bearing IL-2 and Ad-IFN-b was conducted in a pilot and a phase I studies, respectively. Although IL-2 gene transfer to tumors has been experimentally effective, any clinical responses were not observed in the pilot study and no subsequent clinical study has been reported. The phase I study with intrapleural injection of Ad-IFN-b demonstrated tolerance of the patients and activated natural killer cells but not cytotoxic T cells. Although the gene therapy was combined with conventional chemotherapy, some of the malignant pleural mesothelioma patients showed prolonged survival after the treatment. It could be due to immune responses induced by IFN-b secretion and the investigators detected humoral responses against mesothelin, a marker molecule for mesothelium and malignant pleural mesothelioma, to which the antibody was negative in the pretreatment sera. These analyses suggest that the immune system was activated against mesothelin and that a putative tumor antigen could be recognized following tumor cell death. Multiple injections with a high dose of Ad-IFN-b are a possible treatment modality to enhance the anti-tumor effects and a combinatory use of other treatment strategies including low dose chemotherapy that deplete regulatory T cells may contribute to further anti-tumor effects.
Future direction for Malignant Pleural Mesothelioma
Administration of replication-incompetent Ad is safe in clinical settings but the efficacy was not great enough to prolong the survival in most of the cases. Oncolytic Ad is the next to be investigated, which replicate within tumors and infect to the tumor in the vicinity as the progenies released from the destroyed tumors. Currently Ad defective of E1B-55kDa molecules are commercially available in China and many types of oncolytic viruses are investigated at various development stages. Some of them have been clinically tested to demonstrate the feasibility in non-malignant pleural mesothelioma patients. These new typed vector systems can be another virotherapy for malignant pleural mesothelioma treatments.
Correspondence:
Masatoshi Tagawa,
Division of Pathology and Cell Therapy,
Chiba Cancer Center Research Institute.
666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan
Phone: +81-43-264-5431 ext 5101
Fax: +81-43-265-4459
E-mail: mtagawa@chiba-cc.jp
Author Affiliations:
(A) Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan
(B) Department of Molecular Biology & Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
(C) Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan
(D) Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
(E) Department of Surgery, School of Medicine, Toho University, Tokyo, Japan
