New approaches for mesothelioma: Biologics, vaccines, gene therapy, and other novel agents

doi:10.1053/sonc.2002.30234

Seminars in Oncology

Volume 29, Issue 1, February 2002, Pages 82-96

https://doi.org/10.1053/sonc.2002.30234 Get rights and content

Abstract

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)–activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-α), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-γ), IFN-α, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1β transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself. Semin Oncol 29:82-96. Copyright © 2002 by W.B. Saunders Company.

Section snippets

The immunology of malignant mesothelioma

Although malignant mesothelioma is not a classically immunogenic cancer like malignant melanoma or renal cell carcinoma, with their well-described instances of spontaneous regression, there is abundant evidence for immune recognition. Early studies described a relationship between tumor-infiltrating lymphocytes and prognosis, suggesting that if some patients mounted a helpful immune response, similar responses might be induced in other patients.² Occasionally, regression occurs spontaneously,

Gene therapy

The concept of gene therapy evolved from the observation that some disease states can be caused by a single defective gene. In theory, a disease caused by such a defect may be treated by the insertion of a normal copy of the mutant or deleted gene. Although cancer usually occurs as a result of not one, but many genetic mutations in a multistep process, from this simple theoretical beginning gene therapy has evolved to the treatment of cancer patients. Gene therapy in cancer is not restricted to

Mesothelioma vaccines

Cancer vaccines are a form of immunotherapy in which components of the patient's tumor are used to generate a specific immune response. Cancer vaccines may be most useful in situations of low tumor burden, such as in adjuvant therapy of surgically or chemotherapeutically treated disease, or alternatively in high-risk people such as the heavily asbestos-exposed population. Obtaining a response in patients with a high tumor burden may be more difficult.

A primary requirement for development of a

Chemoimmunotherapy

The potential for synergy between chemotherapy and immunotherapy was first noted in the early 1980s, when cytotoxic drugs were administered after tumor vaccination to guinea pigs bearing syngeneic L10 hepatocarcinoma cells. Increased survival was observed, and it was hypothesized that if tumor architecture was disrupted by vaccine-induced inflammation, drug cytotoxicity might be enhanced.⁶⁶ There is a theoretical concern that cytotoxic chemotherapy may impair antigen-specific immune responses,

Vascular endothelial growth factor in mesothelioma

Vascular endothelial growth factor (VEGF) released by tumor cells binds to receptors on endothelial cells, initiating a signaling cascade that results in new blood vessel formation. VEGF signaling through its receptor, flk-1, plays a pivotal role in the angiogenesis and growth of solid tumors, and appears to be important for the progression and prognosis of malignant mesothelioma.⁷⁵ VEGF is an autocrine growth factor for mesothelioma.⁷⁶ Patients with mesothelioma have significantly higher serum

Conclusions and future directions

Although much progress has been made in animal models, in patients, the evaluation of gene therapy, vaccination, immunotherapy, and novel cytostatic agents are still in their infancy. The lack of effective conventional modalities has permitted enrollment of patients in clinical trials of novel therapies at an early stage of disease, and the application of these therapies in malignant mesothelioma has served as a model for other solid tumors. This situation may be changing, as more effective

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Immune checkpoint inhibitor therapy for malignant pleural mesothelioma
2021, Lung Cancer
Mesothelioma is a rare and universally fatal cancer linked to exposure to asbestos. Until recently, standard of care treatment was chemotherapy; a treatment resulting in a minimal survival extension, and not improved upon for almost twenty years. However, the advent of cancer immunotherapy – and in particular the immune checkpoint inhibitor class of drugs - has resulted in recently approved new treatment options, with more currently under investigation.
Here, we review clinical trials of both single agent and combination checkpoint inhibitors in mesothelioma, plus studies investigating their combination with chemotherapy. We also describe current advances in biomarker identification regarding prediction of patient response to checkpoint inhibitors. Finally, we assess the probable future direction of the field; including where current and developing technologies are likely to lead – in terms of both biomarker discovery and treatment options.
Phase i trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma
2014, Clinical Lung Cancer
Citation Excerpt :
The PDGF/PDGFR pathway activates several downstream signaling cascades (c-Src, phospholipase C-λ, phosphotidylinositol-3-kinase/AKT, vascular endothelial growth factor, and Grb2/Sos) that ultimately induce cell proliferation, cell morphologic changes, and antiapoptosis.5 MPM tumor cells express protein PDGF-BB and PDGFRβ, and PDGF has been shown to increase cell proliferation in vitro by murine xenografts with potential autocrine stimulation.6-11 It is theorized that the PDGF pathway exhibits autocrine stimulation in malignant mesothelioma cells.7,9
We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM).
A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels.
Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p-PDGFRα IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRα in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of ≥ 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done.
The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRα inhibitors, is warranted.
Malignant Pleural Mesothelioma: Update on Treatment Options with a Focus on Novel Therapies
2013, Clinics in Chest Medicine
Citation Excerpt :
Other groups showed only limited activity with intrapleural IL-2, and with the combination of intrapleural IFN-γ and autologous activated macrophages. Immunotherapy trials in Australia showed some significant tumor regression with repeated intratumoral injection of granulocyte-monocyte colony-stimulating factor (GM-CSF), but with complications related to the catheters used for cytokine instillation.65–67 In the absence of curative therapies for MPM, several groups have investigated the nascent technologies of gene transfer as a potential mediator of antitumor responses in MPM (Table 1).68
Immunity and malignant mesothelioma: From mesothelial cell damage to tumor development and immune response-based therapies
2012, Cancer Letters
Citation Excerpt :
Their results demonstrated that the vaccine was highly effective in inducing increased cytotoxic T cell populations in MM patients and in generating polyfunctional CD8+ T cell responses in a high proportion of the study subjects with minimal toxicity [164]. A final MM vaccination strategy is the development of cell-based vaccines [165–167]. Mukherjee et al. recently reported the effects of tumor cells transfected with IL-4, IL-2, GM-CSF, B7-1 and allogeneic MHC molecules, showing that cells transfected with B7-1 and GM-CSF were effective as cell vaccines by delaying tumor growth following surgical debulking.
Malignant mesothelioma (MM) is a cancer with a high mortality rate and limited therapeutic options, typically presenting as a tumor in the serous membranes, most frequently in the pleura and the peritoneum rather than in the pericardium. There is much evidence that the immune system contributes to the biogenesis, growth and metastasis of MM through the unbalanced production of oxidants and cytokines, mesothelial cell DNA damage and the active support of MM neoangiogenesis and immunosuppression. Because classical therapeutic approaches are generally ineffective, novel immunological tools are being developed to target the immune cells infiltrating the MM foci and exploit the immune system to elicit an effective anti-tumor response. These therapies work by stimulating local inflammatory cells or transferring exogenously activated immunocompetent cells and by depleting MM-associated immunosuppressive clones to target the spontaneous specific immune responses against MM and to subvert MM-driven immunoediting. This review summarizes the recent evidence on the immune system mechanisms that support MM development and the novel therapeutic approaches for strengthening the immune system by MM immunotherapy that are currently being developed in both experimental models and clinical trials.
Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma
2011, Respiratory Medicine
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MPM shows limited response to conventional chemotherapy and radiotherapy. Although the multi-targeted anti-folate pemetrexed has recently been approved as a first-line agent in combination with cisplatin for the treatment of MPM, overall survival remains very poor5 with a median survival duration of 8–18 months.6 In several centers, potentially curative surgery combined with some form of adjuvant therapy has been performed.
Malignant pleural mesothelioma (MPM) is an aggressive malignant tumor of mesothelial origin associated with asbestos exposure. MPM has a limited response to conventional chemotherapy and radiotherapy so early diagnosis of MPM is very important. Vascular endothelial growth factor (VEGF), a potent mitogen for the vascular endothelium, is also known to be an autocrine growth factor for MPM. Here, we investigated the pleural effusion VEGF levels in patients with MPM and compared them to those of a population with a non-malignant pleuritis or lung cancer involving malignant pleural effusion.
The pleural effusion VEGF concentrations were measured in 46 MPM patients and 45 individuals with non-MPM individuals (25 individuals with non-malignant pleural effusions, and 20 individuals with lung cancer involving malignant pleural effusion).
We demonstrated that patients with MPM had significantly higher pleural effusion VEGF levels than a population with non-malignant pleuritis or lung cancer involving malignant pleural effusion, and the patients with advanced stage MPM showed higher levels of VEGF than the early stage MPM patients. The difference in overall survival between the groups with pleural effusion VEGF levels lower and higher than the assumed cut-off of 2000 pg/ml was significant.
Our data suggest that the pleural effusion VEGF concentration could be useful as an aid for the diagnosis of MPM and as a prognostic factor.
How Our Continuing Studies of the Pre-clinical Inbred Mouse Models of Mesothelioma Have Influenced the Development of New Therapies
2022, Frontiers in Pharmacology

View all citing articles on Scopus

^*: Address reprint requests to B.W.S. Robinson, MD, University Department of Medicine, 4th Floor G block, Sir Charles Gairdner Hospital, Verdun St Nedlands, Western Australia 6009, Australia.

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New approaches for mesothelioma: Biologics, vaccines, gene therapy, and other novel agents*

Abstract

Section snippets

The immunology of malignant mesothelioma

Gene therapy

Mesothelioma vaccines

Chemoimmunotherapy

Vascular endothelial growth factor in mesothelioma

Conclusions and future directions

Lung Cancer

Cancer Lett

Blood

Clin Immunol Immunopathol

Mutat Res

Semin Immunol

Cell

Ann Thorac Surg

Chest

Ann Thorac Surg

Trends Microbiol

Chest

Eur J Cancer

Eur J Cancer

Pharmacol Ther

Surg Oncol

Wittenoom, Western Australia: A modern industrial disaster

Am J Ind Med

Lymphocytic infiltration of pleural mesothelioma and its significance for survival

South Afr Med J

Mesothelioma: Recent studies of growth regulation

Lymphocyte responses to phytohaemagglutinin in patients with asbestosis and pleural mesothelioma

Clin Exp Immunol

Asbestos fibres inhibit the in vitro activity of lymphokine-activated killer (LAK) cells from healthy individuals and patients with malignant mesothelioma

Clin Exp Immunol

High frequency of immune dysfunctions in asbestos workers and in patients with malignant mesothelioma

J Clin Immunol

Molecular pathobiology and immunology of malignant mesothelioma

J Pathol

Asbestos and cancer: Human natural killer cell activity is suppressed by asbestos fibres but can be restored by recombinant interleukin 2

Am Rev Respir Dis

Immunotherapy with BCG vaccine in 30 cases of mesothelioma

South Afr Med J

Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes

J Exp Med

Lysis of human malignant mesothelioma cells by natural killer (NK) and lymphokine-activated killer (LAK) cells

Am Rev Respir Dis

Intralesional cytokine therapy in cancer: A pilot study of GM-CSF infusion in mesothelioma

J Immunother

Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: Persistent transgene expression despite antibody generation

Cancer Gene Ther

Chemosensitivity and cytokine sensitivity of malignant mesothelioma

Cancer Chemother Pharmacol

Comparative studies of human malignant mesothelioma in vivo, in xenografts in nude mice, and in vitro. Cell origin of malignant mesothelioma

Cancer

Potential for interferon-alpha-based therapy in mesothelioma: Assessment in a murine model

J Interferon Cytokine Res

Interferon (IFN)-alpha and IFN-gamma in combination with methotrexate: in vitro sensitivity studies in four human mesothelioma cell lines

Anticancer Drugs

HLA antigen expression and malignant mesothelioma

Am J Respir Cell Mol Biol

Effect of recombinant interferon-beta ser on primary human tumor colony-forming units

J Interferon Res

Intrapleural treatment with recombinant gamma interferon in early stage malignant pleural mesothelioma

Cancer

Interleukin-2 induces cell cycle perturbations leading to cell growth inhibition and death in malignant mesothelioma cells in vitro

J Cell Physiol

Interleukin 2 and lymphokine activated killer cells in malignant mesothelioma

Eur Respir Rev

Intrapleural administration of interleukin-2 for the treatment of patients with malignant pleural mesothelioma: A phase II study

Cancer

Interleukin-12 induces an effective antitumor response in malignant mesothelioma

Am J Respir Cell Mol Biol

Recombinant human interleukin-12 (rhIL-12) in patients with ovarian and gastrointestinal cancers. Evidence of biological activity and lack of significant toxicity with low-dose intraperitoneal (ip) administration

Proc Am Soc Clin Oncol

Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma

J Immunother

Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity

Proc Natl Acad Sci USA

Induction of tumor antigen-specific immunity in vivo by a novel vaccinia vector encoding safety-modified simian virus 40 T antigen

J Natl Cancer Inst