Radio-immunotherapy and chemo-immunotherapy as a novel treatment paradigm in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive neoplasm with poor outcome. Novel radical radiation techniques using intensity modulated radiation therapy (IMRT) have become an important component of therapy in mesothelioma. Immunotherapy also provides new therapeutic options. However, how best to integrate immunotherapy with standard therapy such as radiation, chemotherapy and surgery remains unknown. A change of paradigm from adjuvant normofractionation to induction accelerated hypofractionated hemithoracic radiation could provide a platform to combine immunotherapy due to the potential benefit of short course high dose radiation on the immune system. Immunotherapy can also be combined with chemotherapy. Although chemotherapy is generally considered immunosuppressive, some chemotherapeutic agents do induce cell death that can be immunogenic and stimulate a specific immune response against the tumor. Immunotherapy could also be used in between cycles of chemotherapy to limit tumor cell repopulation and optimize the results of both treatments. The integration of immunotherapy into a multimodality approach is opening new avenue of treatment for mesothelioma.

Keywords: Malignant pleural mesothelioma (MPM); chemotherapy; immunotherapy; radiotherapy; surgery.

Figure 1

Evolution of radical hemithoracic radiation therapy in mesothelioma.

Figure 2

Abscopal effect induced by local radiation can be enhanced when combined with immune checkpoint inhibitors. When local radiation is delivered to the primary tumor, tumor-associated Ag are released from dead tumor cells and processed by APC such as DC. APCs then traffic to the lymph nodes and present Ags to naïve T cells which are activated and start to proliferate. A large number of activated T cells especially CTLs migrate and traffic to the tumor site and exert cytolysis of tumor cells. The SMART approach with an accelerated hypofractionated hemithoracic radiation followed by surgery could therefore provide an excellent platform to introduce immunotherapy in clinical practice. Ag, antigens; APC, antigen presenting cells; DC, dendritic cells; EPP, extrapleural pneumonectomy.

Figure 3

Mesothelioma stem cells (MSC) could be a key target to inhibit repopulation between cycles of chemotherapy. Tumor growth delay can be achieved with chemotherapy, however, tumor grows back rapidly due to cancer cell repopulation between cycles of chemotherapy (blue curve). This hypothesis model assumes that targeting MSC would be able to eliminate cancer cell repopulation during the intervals of chemotherapy (red curve).