Local Therapies and Modulation of Tumor Surrounding Stroma in Malignant Pleural Mesothelioma: A Translational Approach

Abstract

Malignant Pleural Mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated with asbestos exposure and still lacking effective therapies. Modern targeted biological strategies that have revolutionized the therapy of other solid tumors have not had success so far in the MPM. Combination immunotherapy might achieve better results over chemotherapy alone, but there is still a need for more effective therapeutic approaches. Based on the peculiar disease features of MPM, several strategies for local therapeutic delivery have been developed over the past years. The common rationale of these approaches is: (i) to reduce the risk of drug inactivation before reaching the target tumor cells; (ii) to increase the concentration of active drugs in the tumor micro-environment and their bioavailability; (iii) to reduce toxic effects on normal, non-transformed cells, because of much lower drug doses than those used for systemic chemotherapy. The complex interactions between drugs and the local immune-inflammatory micro-environment modulate the subsequent clinical response. In this perspective, the main interest is currently addressed to the development of local drug delivery platforms, both cell therapy and engineered nanotools. We here propose a review aimed at deep investigation of the biologic effects of the current local therapies for MPM, including cell therapies, and the mechanisms of interaction with the tumor micro-environment.

Feasibility and safety of extended pleurectomy/decortication for malignant pleural mesothelioma. A single group experience

“…The role of RT is supposed to acquire greater relevance into the next future multimodal regimens due to both novel techniques and abscopal interaction with immunotherapy, 10–12 which is now going to play a significant role against MPM 13–15 . Although limited, our fundings highlight a rationale for local therapeutic delivery after a starting surgical approach with the aim, on one hand, of acting on the immunoinflammatory pathways which drive MPM progression 16,17 and, on the other hand, of limiting the systemic toxicities of chemo‐ and immunotherapy 18–22 …”

Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects

“…Few strategies for local therapeutic delivery have been developed and tested over the past years in mesothelioma treatment. The major rationale of these therapies is: (i) to diminish the risk of therapeutic agent inactivation before reaching the target tumour mass; (ii) to elevate the concentration of drugs in the tumour microenvironment (iii) to reduce toxicity (43). Development of nanotechnology in biomedicine opens many opportunities in cancer treatment.…”

“…However, the best approach to administer therapies in malignant pleural mesothelioma seems to be the local treatment e.g. pleural injection or inhalation (43). The most tested NPs for MPM treatment are liposomes.…”

“…In malignant pleural mesothelioma treatment, liposomes are used to deliver chemotherapeutics, such as doxorubicin (44,45), or pemetrexed (46,47), with the main objective being to enhance the concentration of active drugs in the peritoneal cavity and to extend the release of the compounds. Ando et al showed that administration into the pleural cavity of pemetrexed inside liposomes resulted in more profound suppressive effect on tumour growth in mesothelioma mouse model, compared to pemetrexed alone (43). Other researchers investigated (48,49) liposomal accumulation in mesothelioma tumour bearing mice and in healthy animals.…”

Immunological Responses to Cancer Therapy

“…Both Lisini et al [5] and Fransen et al [6] describe the possibilities, advantages, and disadvantages of local administration of immunotherapy, the first in the context of mesothelioma, an aggressive form of lung cancer that might benefit from more localized treatment, and the latter in the context of targeting the tumor-draining lymph nodes, highlighting the pivotal role of this immune orchestrating organ. These novel approaches warrant more appreciation, since they target the main areas, tumor and tumor-draining lymph nodes, reduce possible side-effects, and, most importantly, lead to systemic immune responses.…”