Immunotherapy for Malignant Pleural Mesothelioma. Current Status and Future Prospects

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura that is frequently resistant to conventional therapies. Immunotherapy is a promising investigational approach for MPM that has shown some evidence of clinical benefit in select patients. However, tumor-induced immunosuppression is likely a major impediment to achieving optimal clinical responses to immunotherapeutic intervention. MPM contains a variable degree of infiltrating T-regulatory cells and M2 macrophages, which are believed to facilitate tumor evasion from the host immune system. Additional immunosuppressive factors identified in other human tumor types, such as tumor-associated programmed death ligand-1 expression, may be relevant for investigation in MPM. Conventional cytoreductive therapies, such as radiation, chemotherapy, and surgery, may play a critical role in successful immunotherapeutic strategies by ablating intratumoral and/or systemic immunosuppressive factors, thus creating a host environment more amenable to immunotherapy. This article reviews the immunotherapeutic approaches being evaluated in patients with MPM and discusses how immunotherapy might be rationally combined with conventional tumor cytoreductive therapies for this disease.

The role of intracavitary therapies in the treatment of malignant pleural mesothelioma

“…Based on preliminary clinical evidences, immunotherapy has been proposed as a valuable option for intrapleural treatment of MPM (28). Both interferons (IFNs) and IL-2 have been used as intrapleural agents.…”

Current and prospective pharmacotherapies for the treatment of pleural mesothelioma

“…Generally, combination treatments of different chemotherapeutic drugs have shown more effective outcomes 17 . One combination that has been shown to achieve a slight improvement of survival is combination of pemetrexed with cisplatin 18,19 . However, although this study was an improvement in survival (of 2.8 months), successful therapy for MPM is obviously still lacking.…”

“…There are numerous approaches to passive immunotherapy such as the use of cytokines, monoclonal antibodies, and activated T-lymphocytes 18,21 . It has been shown that cytokines such as interleukins stimulate the immune system against viruses and tumours, and it is hypothesised that this stimulation could be harvested to reduce tumour growth.…”

“…One phase II study utilised interleukin-2 treatment for mesothelioma patients and found that those who responded to therapy had a statistically significant increase in median survival compared to non-responders 25 . However, conflicting findings on interleukin-2 treatment have been reported 18 , potentially due to different administration methods, and toxicity and side-effects of interleukin-2 treatment have been reported 26 This and the conflicting reports provide a clear example of the challenge of harnessing the power of the immune system.…”

Diagnóstico y tratamiento del mesotelioma pleural maligno

“…La tendencia actual se orienta a investigar nuevas dianas terapéuticas centradas en controlar angiogénesis y vías apoptóticas a través de ligandos específicos, incluyendo platelet derived growth factor (PDGF, que se sobreexpresa con bastante frecuencia en el mesotelioma y se asocia a menor supervivencia) y mesotelina (que se expresa solo en el subtipo epitelial) entre otros 75,76 . También dentro de la terapia multimodal la inmunoterapia puede ejercer un importante papel en el tratamiento del mesotelioma, porque este tumor es capaz de evadir el sistema inmune a través de células T-reguladoras (Treg) y macrófagos M2, y nuevas estrategias terapéuticas que combinan la citorreducción quirúrgica, quimioterapia, inmunoterapia y radioterapia pueden conseguir un mejor control de la enfermedad 77 . Desde la inmunoterapia pasiva (usando citoquinas o anticuerpos específicos) hasta la modulación de la respuesta inmune mediante células dendríticas u otras, hay un amplio espectro de posibilidades para conseguir efectos antitumorales marcadamente sinérgicos [78][79][80] .…”