Targeting immune checkpoints: New opportunity for mesothelioma treatment?

Highlights

• Working mechanism and expression pattern of immune checkpoints.

• Clinical data of immune checkpoint blocking antibodies are very promising.

• Immune checkpoint blockade deserves further investigation in mesothelioma.

• Future opportunities for research on immune inhibitory molecules.

Abstract

Malignant pleural mesothelioma is an aggressive cancer linked to asbestos exposure in most patients. Due to the long latency between exposure and presentation, incidence is expected to further increase in the next decade, despite the ban on asbestos import which occurred at the end of last century in industrialized countries. Platinum-based palliative chemotherapy is the only treatment with proven benefit on outcome, resulting in selected patients in a median overall survival of about 1 year. Therefore, there is room for therapeutic improvement using a new strategy to prolong survival. Dealing with cancer cell induced immunosuppression is a promising approach. Reactivating immune responses that are silenced by immune checkpoints recently gained a lot of interest. Checkpoint blockade has already shown promising preclinical and clinical results in several cancer types and is currently also being investigated in mesothelioma. Here, we discuss the expression patterns and mechanisms of action of CTLA-4 and PD-1 as the two most studied and of TIM-3 and LAG-3 as two interesting upcoming immune checkpoints. Furthermore, we review the clinical results of molecules blocking these immune checkpoints and point out their future opportunities with a special focus on mesothelioma.

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive and nearly always fatal cancer, causally linked to previous, mostly professional, exposure to asbestos [1]. The highest incidence rates, around 30 cases per million inhabitants, are reported for Australia, Belgium and the UK [2], [3]. The incidence of MPM is still expected to increase over the next decades due to the long latency between exposure to asbestos and diagnosis and because asbestos is still being used in developing countries [4]. The prognosis of MPM patients remains poor with a median overall survival time in untreated patients of about 10 months and a 5 year survival rate of less than 5% [4], [5]. Palliative platinum–antifolate chemotherapy is the only treatment with proven improvement of outcome in MPM, resulting in a median survival of about 1 year. There is therefore a need for new therapeutic strategies. The discovery of immune checkpoint receptors such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and more recently programmed death-1 (PD-1) introduced a new, exciting era in cancer immunotherapy [6]. Immune checkpoints are responsible for controlling and inactivating the immune system in order to avoid autoimmunity and prevent collateral tissue damage [7]. The new paradigm consists of reactivating silenced immune responses by neutralizing molecules that induce T-cell exhaustion and immune tolerance. Immune checkpoint blocking antibodies have already shown promising results in several cancer types [8], [9], [10], [11], [12], [13]. Recently antibodies blocking immune checkpoints are being investigated in mesothelioma patients. In this review, we discuss the expression pattern and mechanisms of action of CTLA-4 and PD-1 as the two most studied checkpoint receptors and of T-cell immunoglobulin mucin-3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) as two interesting upcoming immune checkpoints. Furthermore, we review the clinical results of therapeutic molecules blocking these immune checkpoints with primary focus on CTLA-4 and PD-1 since FDA approved antibodies are available for both of them. Future opportunities of immune inhibitory molecules will be pointed out, with a special focus on MPM.