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Introduction: Malignant mesothelioma is a rare and lethal malignancy primarily affecting the pleura and peritoneum. Mesothelioma incidence is expected to increase worldwide and current treatments remain ineffective, leading to poor prognosis. Within this article potential targets to improve the quality of life of the patients and assessment of further avenues for research are discussed.\ud \ud Areas covered: This review highlights emerging therapies currently under investigation for malignant mesothelioma with a specific focus on phase I and phase II clinical trials. Three main areas are discussed: immunotherapy (immune checkpoint blockade and cancer vaccines, among others), multitargeted therapy (such as targeting pro-angiogenic genes) and gene therapy (such as suicide gene therapy). For each, clinical trials are described to detail the current or past investigations at phase I and II.\ud \ud Expert opinion: The approach of applying existing treatments from other cancers does not show significant benefit, with the most promising outcome being an increase in survival of 2.7 months following combination of chemotherapy with bevacizumab. It is our opinion that the hypoxic microenvironment, the role of the stroma, and the metabolic status of mesothelioma should all be assessed and characterised to aid in the development of new treatments to improve patient outcomes.

Introduction: Tremelimumab demonstrated therapeutic activity in different malignancies, including malignant pleural mesothelioma (MPM); however, continued research could improve the therapeutic index of this agent.\ud \ud Areas covered: This review describes tremelimumab’s clinical efficacy, administration and safety in patients affected with MPM and reports the state of the art clinical trials of tremelimumab. A literature search using the PubMed database was conducted using the search terms tremelimumab, MPM, current therapy, immune checkpoint blockage and cytotoxic T lymphocyte-associated antigen-4. Data was also obtained from meeting abstracts and clinical trial registries.\ud \ud Expert opinion: The use of immunotherapy has been extended from melanoma to thoracic malignancies or lung cancer and MPM. The first clinical trials for MPM with drugs modulating immune checkpoints have been tested or are currently being tested with the first results now under critical consideration. Among these drugs, tremelimumab has been attracting attention as a potential new treatment for MPM. Nevertheless, even though clinical efficacy has been preliminarily demonstrated, the cost/benefit ratio of this drug for this neoplasm is yet to be ascertained.

Malignant pleural mesothelioma is a highly invasive tumor arising from the mesothelial cells of serosal surfaces. Several chemotherapeutic agents have been tested for the treatment of this disease and doublet cisplatin with antifolates has been demonstrated to have significant efficacy in Phase III studies. However, the benefit of these treatments remains poor and the median survival time of patients is low, ranging between 9 and 17 months. Targeted therapies are being developed in oncology and emerging evidence suggests that they offer disease control in several tumors. This article reviews the knowledge on the malignant pleural mesothelioma molecular pathway and focuses on results of clinical trials conducted on this devastating disease.

Camillo Porta1, Chiara Paglino1, Luciano Mutti21Medical Oncology and Laboratory of Pre-Clinical Oncology and Developmental Therapeutics, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy; 2Local Health Authority 6, Piedmont, ItalyAbstract: Ribonucleases are a superfamily of enzymes which operate at the crossroads of transcription and translation, catalyzing the degradation of RNA; they can be cytotoxic because the cleavage of RNA renders indecipherable its information. Ranpirnase is a novel ribonuclease which preferentially degrades tRNA, thus leading to inhibition of protein synthesis and, ultimately, to cytostasis and cytotoxicity. Ranpirnase has demonstrated antitumor activity both in vitro and in vivo in several tumor models. The maximum tolerated dose emerging from phase I studies was 960 g/m2, with renal toxicity as the main dose-limiting toxicity. A large phase II trial showed that ranpirnase has disease-modifying activity against malignant mesothelioma. Ranpirnase proved to be superior to doxorubicin in a phase III trial, while preliminary results of another large, phase III trial, suggest that the combination of ranpirnase and doxorubicin could be more effective than doxorubicin alone. In all the above studies, ranpirnase seems to act mainly as a cytostatic rather than a cytotoxic drug, stabilizing progressive disease and potentially prolonging patients’ survival. Ranpirnase may thus find its niche in combination with doxorubicin for mesothelioma as a second-line therapy, where no standard of care presently exists.Keywords: ranpirnase, mesothelioma, ribonucleases, doxorubicin, antitumor activity