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(Chest. 1999;116:455S-460S.)
© 1999 American College of Chest Physicians

Emerging Translational Therapies for Mesothelioma*

Harvey I. Pass, MD, FCCP; Bruce W. Robinson, MD; Joseph R. Testa, PhD and Michele Carbone, MD, PhD

* From the Karmanos Cancer Institute, Wayne State University, Detroit, MI (Dr. Pass); University of Western Australia, Perth, Australia (Dr. Robinson); Fox Chase Cancer Center, Philadelphia, PA (Dr. Testa); and Cardinal Bernardin Cancer Center, Loyola University, Maywood, IL (Dr. Carbone).

Correspondence to: Harvey I. Pass, MD, FCCP, Harper Hospital, 3990 John R, Suite 2102, Detroit, MI 48201;


   Abstract
TOP
 Abstract
Introduction
 Types of Novel Therapies
 Translational Bench-Work...
 Future Directions
 References
 
Malignant pleural mesothelioma remains a therapeutic and diagnostic problem. Translational mechanisms for treatment of the disease are emerging from newly learned characteristics of the tumor on a molecular, cellular, and extracellular basis. Although slow to reach the clinical arena, these potential strategies do show proof of principle in the in vitro and in vivo settings, and some, including adenoviral molecular chemotherapy, have completed phase I testing. This review describes the rationale and status of these newer treatment ideas.


   Introduction
TOP
 Abstract
 Introduction
Types of Novel Therapies
 Translational Bench-Work...
 Future Directions
 References
 
There has been a flurry of interest in the development of novel strategies for malignant pleural mesothelioma (MPM). This interest is primarily because of (1) greater safety of an aggressive cytoreductive surgical approach to the disease; (2) the intracavitary nature of the disease that would allow intrapleural delivery of innovative techniques either at the time of cytoreductive surgery, postoperatively, or in the nonsurgical candidate with an intact pleural cavity; and (3) greater recognition of consistent genetic and immune abnormalities for MPM. Considering the median survival of 8 to 18 months from the time of diagnosis for patients with MPM, any novel therapy that improves on the lack of response with standard chemotherapy and radiation therapy would be welcome.


   Types of Novel Therapies
TOP
 Abstract
 Introduction
 Types of Novel Therapies
Translational Bench-Work...
 Future Directions
 References
 
Novel therapies for mesothelioma are slowly being introduced to the clinic after preclinical investigations in vitro and in vivo. A number of trials are oriented more toward intracavitary adjuncts at the time of cytoreduction. These have evolved from the use of the new therapies at other anatomic sites with adaptation to the pleura. These intracavitary approaches include photodynamic therapy1 and hyperthermic perfusion with or without cytotoxic agents.2 Another set of novel therapies stresses new drug combinations that have shown promise in phase I/II studies. Many of the newer, more innovative translational bench-work investigations have a molecular biological or immunotherapeutic flavor. It is this last category of novel therapies that we will discuss in this review.


   Translational Bench-Work Investigations
TOP
 Abstract
 Introduction
 Types of Novel Therapies
 Translational Bench-Work...
Future Directions
 References
 
This broad category of novel therapies includes gene therapy approaches. The use of gene therapy in mesothelioma can be divided into a number of different categories, including (1) molecular chemotherapy, (2) autocrine/paracrine interference, (3) genetic immunopotentiation, or (4) mutation compensation.

Molecular Chemotherapy
Molecular chemotherapy is synonymous with the use of suicide genes. The principle involved in this treatment is the delivery of DNA via some vector that is usually viral or nonviral. Nonviral methods include the direct injection of DNA into cells; incorporation of DNA into cationic liposomes that will nonspecifically enter target cells; precipitation of DNA with calcium phosphate, which is then endocytosed by the cells with transport to the nucleus; or application of a short, high voltage to cells, forming pores that will allow the DNA to move into the cells. Obviously, these methods have limited application in vivo and are nonspecific with regard to targeting. More specific nonviral methods include receptor-mediated transfer of DNA by complexing DNA with antibody conjugates, which, after recognition of a specific moiety on the cell surface, can then be taken into the cell and incorporated.

More commonly, viral delivery systems have been used for in vivo gene delivery, and the emphasis has been on the retroviral or adenoviral vectors. Using a packaging cell line as a "production factory," a retroviral vector will contain the DNA of interest and then infect a target cell line. The retroviral vector, however, does not contain the necessary genes to replicate itself. Nevertheless, once the retroviral vector enters the cell, it is essentially incorporated into the DNA of the host cell and the DNA of interest (which hopefully has an impact on the cancer) is then expressed, but the structural retroviral proteins are not. Retroviral constructs are appealing because they are incorporated only into proliferating cells (ie, neoplastic cells), and theoretically will not cause production of the structural viral proteins that could then elicit an immunologic response and abrogate the antitumor effect. For these constructs to work, there must be appropriate receptors on the cancer cells, and large amounts are needed. Moreover, safety concerns involve the possible development of replication-competent virus through homologous recombination. Unfortunately, however, retroviral delivery of DNA requires high titers of the virus and in vivo lability, and it is difficult to deliver foreign DNA sequences > 6 kilobases.

Replication-incompetent adenoviral vectors represent an alternative to retroviral vectors. These vectors contain the integrated DNA that will have the "negative effect" on the cancer. With adenoviral vectors, the DNA can be released into target cells that do not have to be actively proliferating. Eventually, there is translation of the protein coded for by the gene of interest, as well as production of the structural adenoviral genes. There is no integration of the DNA into the chromosome of the host cell, and this failure of integration could affect the long-term expression of the gene. There is usually a high efficiency of transduction, with protein expression and greater in vivo stability than retroviral vectors. Unfortunately, the products of the adenoviral protein infecting the cells may not only elicit an immune response, possibly influencing expression of the foreign DNA, but also may influence normal cell function. Finally, it is not totally clear whether a low level of replication of recombinant adenovirus occurs despite the fact that the replication mechanism has been removed from the vector.

Even in the absence of a particular target, researchers can incorporate DNA into a cancer cell that causes the cell to die when an exogenous factor (such as a drug) is added. An example of such a gene that modifies the cell is the herpes simplex thymidine kinase (TK) gene. Herpes simplex is a virus that is killed by the antiviral ganciclovir. By transferring the herpes simplex TK gene to a tumor virus by infecting it with an adenovirus construct containing the TK gene (ADHSVTK), one essentially can convert the tumor to be just like a herpes virus and then allow for its destruction with ganciclovir. This therapy was the subject of a recently completed phase I trial at the University of Pennsylvania. The goals were to assess the safety, toxicity, and maximally tolerated dose of intrapleural ADHSVTK, to examine patient inflammatory response to the viral vector, and to evaluate the efficiency of intratumoral gene transfer. Twenty-one previously untreated patients were enrolled in this viral titer dose-escalation study. A replication-incompetent recombinant adenoviral vector containing the HSVTK gene under control of the Rous sarcoma virus promoter-enhancer was introduced into the pleural cavity of patients with malignant mesothelioma, followed by 2 weeks of systemic therapy with ganciclovir at a dose of 5 mg/kg bid. The initial 15 patients underwent thoracoscopic pleural biopsy before and 3 days after vector delivery. The last six patients underwent only the post-vector instillation biopsy. Dose-limiting toxicity was not reached. Side effects were minimal and included fever, anemia, transient liver enzyme elevations, and bullous skin eruptions, as well as a temporary systemic inflammatory response in those receiving the highest dose. Strong intrapleural and intratumoral immune responses were generated. Using RNA polymerase chain reaction, in situ hybridization, immunohistochemistry, and immunoblotting, HSVTK gene transfer was documented in 11 of 20 assessable patients in a dose-related fashion.3

A similar approach is under investigation by the group at Louisiana State University.4 5 6 In in vitro mixing experiments, gene-modified ovarian cells killed both mouse and human mesothelioma cells in a dose-dependent manner. Use of the HSV-TK ovarian cells also prolonged survival of mice with MPM in a dose-dependent fashion. These data have served as the basis for an ongoing phase I clinical gene therapy trial for MPM to determine the maximal tolerated dose of HSV-TK-transduced ovarian cancer cells infused into the pleural cavities of mesothelioma patients followed by systemic administration of ganciclovir.

Autocrine and Paracrine Interference
There are a number of autocrine and paracrine pathways involved in the proliferation of mesothelioma, and in our own analysis of mesothelioma, we found that the majority of the cell lines could grow in a serum-free environment and produce significant amounts of cytokines and growth factors, including granulocyte-macrophage colony-stimulating factor, platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and interleukin (IL)-6.7 The association between thrombocytosis and mesothelioma has led to a search for increases in circulating concentrations of cytokines, such as IL-3, IL-4, IL-6, IL-11, granulocyte-macrophage colony-stimulating factor, and erythropoietin. Elevated levels of IL-6 and granulocyte-macrophage colony-stimulating factor have been found in both body fluids and cell lines of mesothelioma patients.8

The targeting of these growth pathways has been the subject of a number of preclinical studies attempting to treat mesothelioma by interfering with growth factor production or their receptors. The relationship between cell transformation and PDGF-ß was first recognized when the ß-peptide chain was found to be homologous with the viral oncogene v-sis. Fibroblasts can be transformed to malignant phenotypes when transfected with the oncogene v-sis. Gerwin et al9 and others have described the increased expression of RNA for both the {alpha}- and ß-chains of PDGF in mesothelioma cell lines and were able to correlate this with increases in PDGF-like activity by the cells. Versnel et al10 11 further corroborated these findings but noted that the elevation was primarily in the ß-chains of PDGF. Malignant mesothelioma cells have been found to possess specific receptors for PDGF-ß while lacking the expression of {alpha} receptors. This is in marked contrast to normal mesothelial cells that have {alpha} receptors and few or no ß receptors.

Transforming growth factor ß (TGF-ß) is another growth-regulatory and immunomodulatory cytokine, and high levels of TGF-ß have been described in several human and mouse malignant mesothelioma cell lines. TGF-ß may have a potential role in regulation of the differential PDGF receptor expression in MPM and thus have an effect on proliferation as well as other events. TGF-ß causes downregulation of a low PDGF-{alpha} receptor messenger RNA (mRNA) concentration in malignant mesothelioma cell lines.12

Antisense strategies have been used to sort out these autocrine and paracrine mechanisms and may have implications for future therapy. Antisense technology involves the construction of a complementary DNA clone for the targeted gene that is fused in the reverse orientation to a promoter. When the antisense mRNA molecules are produced, they are complementary to the normal mRNA molecules, making them unavailable for protein translation. For preclinical work, antisense oligonucleotides (ODN) not linked to a promoter can also be used. Antisense ODN, targeted against specific TGF-ß mRNA, have been used to block TGF-ß production from MPM cells in vitro and in vivo. TGF-ß2 mRNA concentrations and TGF-ß2 protein secretion from the cell lines were reduced after exposure to TGF-ß2 antisense ODN. Moreover, MPM cell proliferation was inhibited by both TGF-ß1- and TGF-ß2-specific antisense ODN, and administration of TGF-ß2 antisense ODN delivered locally reduced tumor growth in vivo.13

IGF is another of the important autocrine loops in MPM. IGFs are important regulators of cell growth and development, and a number of human tumors and tumor cell lines secrete IGF-1 or IGF-2 and express the appropriate IGF receptor (IGF-1R and IGF-2R, respectively).14 It is hypothesized that some of these tumors may rely on paracrine or autocrine mechanisms for progression, and a number of studies have demonstrated tumor suppression in vitro and in vivo by interfering with such loops using neutralizing antibody to ligand or receptor, IGF-1 peptide analogs, antisense RNA against IGF-1 or its receptor,15 16 17 or dominant negatives.18 Rutten et al19 have reported that normal rat mesothelial cells, as well as cell lines derived from spontaneous rat mesotheliomas, were found to express transcripts for IGF-2, but cell lines derived from asbestos-induced rat mesotheliomas did not. All mesothelial lines, however, expressed both IGF-1R and IGF-2R. In humans, normal mesothelium, as well as MPM cell lines, expresses IGF-1 and IGF-1R mRNA (by Northern blot or reverse transcriptase polymerase chain reaction), and IGF-1 protein is detected in their conditioned media.20 These studies suggest that MPM growth, both in humans and in animal models for the disease, may involve the IGFs. Pass et al21 investigated this possibility by constructing sense and antisense clones of hamster mesothelioma cells by electroporation, using inducible expression vectors (under the transcriptional control of heat shock promoter 70 containing a complementary DNA fragment corresponding to base pairs 1–309 of IGF-1R in the sense or antisense orientation. In vitro growth of the antisense clones was significantly decreased compared with the sense clones. Sense clones resulted in greater numbers of tumors in vivo compared with the antisense clones. This inhibitory effect of IGF-1R antisense transcripts on mesothelioma may also have implications for the therapy of human mesothelioma.

Immunopotentiation: Genetic or Exogenous
Immunomodulation in mesothelioma patients essentially uses the immune mechanisms so that the tumor will be destroyed by T lymphocytes, macrophages, natural killer cells, or eosinophils. Moreover, by enhancing the patient’s own immune mechanisms through exogenously delivered immune-modulating molecules, the tumor cell may not escape immune surveillance. As detailed above, certain immune-suppressing cytokines, including the TGFs, have been identified in mesothelioma, and their expression can affect survival in preclinical studies. When interferon-{alpha} is delivered intraperitoneally in animals with mesothelioma, survival is prolonged and there is a downregulation of TGF.22

There have been a number of clinical trials that have investigated the role of immunotherapy for mesothelioma, either given systemically or intrapleurally. These trials have assessed the response rates after systemic administration of interferon-{alpha}, -ß, or -{gamma}, or systemic therapy with IL-2 and lymphokine-activated killer cells. In a Southwest Oncology Group study, there were no complete or partial responses using IM interferon-ß for 5 consecutive days for 6 weeks.23 Interferon-{gamma} has had intriguing results by the intrapleural route as documented by Boutin et al.24 Interferon was administered at a dose of 40 million units twice a week for 8 weeks intrapleurally via a catheter or an implantable port to 89 patients during 46 months. Thoracoscopic or surgical biopsy was performed if CT scan 2 weeks after the end of treatment demonstrated a reduction in tumor size. Eight histologically confirmed complete responses and nine partial responses with a >= 50% reduction in tumor size were obtained. The overall response rate was 20%. The response rate for patients with stage I disease was 45%, with the main adverse effects being hyperthermia, liver toxicity, neutropenia, and catheter-related infection.

IL-2-based regimens have also been exploited in mesothelioma. Stoter et al25 treated 14 mesothelioma patients with intrapleural IL-2 and recorded three partial responses. Significant systemic toxicity, however, was seen in a separate combination IL-2–lymphokine-activated killer cell protocol in four patients without corresponding efficacy.26 The largest experience to date with intrapleural IL-2-based therapy has been reported by Astoul et al.27 Intrapleural IL-2 (21 x 106 IU/m2/d for 5 days) was administered to 22 patients with MPM. Three patients had stage IA disease, 1 had stage IB, 16 had stage II, 1 had stage III, and 1 had stage IV (Butchart classification). Patients were evaluated for response 36 days after treatment by CT scan and thoracoscopy with biopsies. There were 11 partial responses and 1 complete response. Stable disease occurred in three patients and disease progression in seven patients. The overall median survival time was 18 months, and the 24-month and 36-month survival rates for responders were 58% and 41%, respectively.

With the demonstration that there may be efficacious results with exogenously delivered immunomodulatory molecules, an interest in using gene therapy to augment immune responses to these tumors has been explored. The mechanisms for genetic immunopotentiation are numerous. One such mechanism exploits the possibility for increased local levels of a cytokine gene product such as IL-2. Increased levels of IL-2 could increase T-cell and natural killer cell proliferation and activity, alter antigen presentation by the tumor, or activate local effector cells.28 Robinson et al28 used a vaccinia IL-2 construct directly intratumorally three times weekly (107 plaque forming units/dose) in six patients. Although vaccinia IL-2 mRNA was maximal 24 to 72 h after treatment, no tumor regression occurred.

A second mechanism for genetic immunopotentiation may involve increasing endogenous major histocompatibility complex (MHC) class antigen presentation or through introduction of foreign MHC I into the tumor.29 Other mechanisms for genetic immunopotentiation could use the introduction of costimulatory molecules into the tumor to augment T-cell proliferation or attempt to decrease immunosuppressive factors. When the B7–1 costimulatory molecule gene was introduced into a nonimmunogenic murine mesothelioma cell line that constitutively expressed high concentrations of class I MHC and TGF-ß, tumor development by two of the four B7–1 transfectant clones was markedly delayed. Enhanced B7–1 expression in this nonimmunogenic tumor cell line promoted the generation of tumor-specific cytotoxic T lymphocytes with consequent retardation of tumor development and coexpression of MHC class II. The specificity of this effect was illustrated by the finding that tumor growth retardation was limited to the B7–1 costimulatory molecule inasmuch as tumors developed when B7–2 was used.30

Finally, vaccination strategies with tumor-specific antigens could be used. Most recently, it has been hypothesized that the expression of viral proteins, specifically large T antigen (Tag) by mesothelioma cells,31 32 33 could be exploited to produce Tag-specific cytotoxic T lymphocytes and to test their efficacy in animal models of virus-induced mesothelioma.34 Various vaccination strategies have been compared for their ability to elicit antigen-specific tumor immunity, using an SV40-BALB/c murine tumor system. Mice have been injected with either baculovirus-derived recombinant SV40 Tag (rTag), with synthetic peptides corresponding to B-cell epitopes on SV40 Tag, or with a plasmid DNA construct encoding the gene for SV40 Tag. In vivo tumor immunity has been determined by a lethal tumor challenge with syngeneic SV40-transformed tumor cells. SV40 Tag-specific antibody titers have been induced in mice immunized with rTag or Tag synthetic peptides, and partial tumor protection has been observed in mice that have been immunized with SV40 Tag peptides. Complete tumor immunity has been observed in mice immunized with rTag. Although protective tumor immunity has also been observed in mice immunized with DNA, negligible levels of antibodies to SV40 Tag have been detected. Examination of the cytotoxic T lymphocyte activity in mice injected with the SV40 Tag-DNA construct revealed Tag-specific lysis of syngeneic SV40-transformed tumor cells. Conversely, little to no cytotoxic T-lymphocyte activity has been detected in mice immunized with rTag. However, antigen-specific antibodies from rTag-immunized mice are capable of mediating antibody-dependent cell-mediated cytotoxicity against SV40-transformed cells.35 36 37 38 39 40

Using an SV40-induced hamster mesothelioma in vivo model, Pass and Carbone have been able to demonstrate protection against tumor development if animals are vaccinated with recombinant Tag (unpublished data, June 1996). Most recently, these findings have been corroborated using a vaccinia Tag construct in a Tag-expressing murine model.41 A novel vaccinia virus construct encoding SV40 Tag (vac-mTag) elicited an immune response in C57BL/6 and BALB/c mice, as manifested by an SV40 Tag-specific cytolytic T-lymphocyte activity against syngeneic (identical genetic background) SV40 Tag-expressing tumor targets. Immunization of mice with a single dose of vac-mTag resulted in potent protection against subsequent challenge with a lethal mouse cancer expressing SV40 Tag. In addition, single-dose vac-mTag immunization coadministered with IL-2 produced a possible therapeutic effect against a preadministered microscopic (but lethal) burden of Tag-expressing tumor cells in vivo. Thus, vac-mTag could be exploited in the therapy of human cancers such as mesothelioma, which are thought to be associated with SV40.

Mutational Compensation
There have been a number of abnormalities of tumor suppressor genes associated with malignant mesothelioma, including the overexpression of the Wilms’ tumor gene,42 43 homozygous deletion of the p16/CDKN2A gene,44 gene mutations of the neurofibromatosis type 2 gene,45 or posttranslational inactivation of the gene product (the retinoblastoma [Rb] gene46 and p5347 ). Gene therapy to target such abnormalities have thus far included preclinical efforts to replace losses of genetic material and restoration of function. Procopio et al48 have reported that massive apoptosis occurred in four mesothelioma lines when they were infected with an adenovirus wild-type p53 construct. There was increased survival in nude mice that received intraperitoneal injections of the construct both before and after inoculation with human mesothelioma. Likewise, Frizelle et al49 have demonstrated the efficacy of p16 replacement in MPM. After transduction with a p16INK4a-expressing adenovirus (Adp16), overexpression of p16INK4a in mesothelioma cells resulted in cell-cycle arrest, inhibition of pRb phosphorylation, diminished cell growth, and eventual death of the transduced cells. Expression of p16INK4a protein was accompanied by decreased expression of pRb, as detected by immunoblot and immunohistochemistry. Experiments in mesothelioma xenografts demonstrated inhibition of tumor formation, tumor growth arrest, and diminished tumor size and spread.


   Future Directions
TOP
 Abstract
 Introduction
 Types of Novel Therapies
 Translational Bench-Work...
 Future Directions
References
 
As described in the previous discussions, there is a wealth of potential molecular and immunotherapeutic targets for mesothelioma that are presently under investigation. Future strategies will certainly target angiogenic mechanisms in MPM because investigators have described alterations in the vascular endothelial growth factor loop in this disease.50 51 Abnormalities of tumor stromal interactions and the extracellular matrix resulting in a propensity for local invasion and metastasis formation have also been described.51 52 53 54 55 56 Moreover, the association of pleural mesothelioma with certain extracellular matrix proteins could have an impact on gene therapy efficiency.57

In addition to the aforementioned specific abnormalities of chromosomes 9 and 22, there are other areas of frequent deletions within chromosome arms 1p, 3p, 6q, and 15q,58 59 and a high frequency of allelic loss from each of these chromosomal sites.60 These sites may hold the answer to other mechanisms for targeting mesothelioma development and growth, and, hopefully, the human genome project may give further insights as to the significance of these abnormalities.61


   Footnotes
 
Abbreviations: IGF = insulin-like growth factor; IGF-1R = IGF-1 receptor; IGF-2R = IGF-2 receptor; IL = interleukin; MHC = multihistocompatibility complex; MPM = malignant pleural mesothelioma; mRNA = messenger RNA; ODN =oligonucleotides; PDGF = platelet-derived growth factor; rTag = recombinant T antigen; Tag = T antigen; TGF = transforming growth factor; TK = thymidine kinase


   References
TOP
 Abstract
 Introduction
 Types of Novel Therapies
 Translational Bench-Work...
 Future Directions
 References
 

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