Current and prospective pharmacotherapies for the treatment of pleural mesothelioma

Abstract

IntroductionMesothelioma is a rare asbestos-linked cancer with an expected incidence peak between 2015-2030. Therapies remain ineffective, thus developing and testing novel treatments is important for both oncologists and researchers. Areas CoveredAfter describing mesothelioma and the shortcomings of current therapies, the article discusses numerous therapies in turn such as immunotherapy (passive and active), gene therapy (such as suicide gene therapy) and targeted therapy such as tyrosine kinase inhibitors. The bases for different therapies and clinical trials at different phases are also described. The article concludes by detailing possible reasons for therapy failure. Expert OpinionDespite the many attempts to uncover new therapeutic options, mesothelioma is still an orphan disease, complicated by factors such as the inflammatory microenvironment and low mutational load. Our opinion is that uncovering the biological mechanisms behind mesothelioma development will assist therapy development. The lack of efficacy of tyrosine kinase inhibitors and modest anti-angiogenic activity indicates a less relevant role for tumour cell proliferation and neoangiogenesis, thus the shortcut of treating mesothelioma with therapies from other cancers may be unsound. Conversely, many lines of evidence indicate that focussing on the survival mechanisms that tumour cells exploit may yield better therapeutics, particularly nutrition and cellular machinery.

Promising investigational drug candidates in phase I and phase II clinical trials for mesothelioma

“…Another class of adoptive immunotherapy is the use of tumour infiltrating lymphocytes (TILs) which are engineered in vitro with affinity T cell receptors against major tumour antigens. One application of TIL therapy is using TILs in combination with high-dose interleukin-2 which has demonstrated a activity in several clinical trials, showing durable clinical response rates near 50% or more, though toxicities and side effects associated with interleukin-2 treatment have also been observed 54,55 .…”

Immunotherapy advances for mesothelioma treatment

“…Immunotherapy is an innovative approach that, rather than targeting cancer cells themselves via drug treatment, aims to stimulate the immune system to promote an anti-tumour immune effect [31]. Specific to MPM, the potential application of immunotherapy may be sound given that it has been shown that lymphocyte infiltration within the tumour mass correlated with improved patient prognosis [32,33].…”

“…Cytokine administration was among the first therapeutic interventions in the treatment of cancer, though its use as a monotherapy has fallen significantly out of favour and it is now generally used in combination therapy [36]. Cytokine administration aims to provide a shortterm "boost" to anti-tumour effects through temporary stimulation of the host's immune system [32]. Table 3.…”

“…The overarching principle behind the use of mAbs in cancer therapy is to target cancerspecific or cancer-associated antigens which the antibody binds to, ultimately resulting in an anti-tumour effect through a variety of mechanisms[36]. For mesothelioma, common antibody targets include mesothelin (highly expressed in mesothelioma) and TGF-β[32].Monoclonal antibodies may be combined with other therapeutics to serve, for example, as vehicles for drugs.Mesothelin represents an interesting target as its high level of expression in mesothelioma results in it commonly being used as a serum biomarker for mesothelioma diagnosis[55] and thus there are several trials investigating its potential as a biomarker. Comparatively, TGF-β is an interesting protein as in normal epithelial cells it is a potent growth inhibitor and promotes cellular differentiation.…”

“…inhibition (through either targeting PD1 itself or its ligands) have also been assessed in clinical trials and currently pembrolizumab and nivolumab are approved for the treatment of metastatic melanoma[32,45]. mesothelioma was DETERMINE, which as of data presented at ASCO 2016 consisted of 571 patients randomised to either placebo (n=189) or treated with tremelimumab (n=382) as a second-or third-line therapy[46].…”