Potential Applications of Immune Checkpoint Blockade for Mesothelioma

Aaron S. Mansfield MD, Tobias Peikert, MD
Published: Wednesday, Jan 28, 2015
Aaron S. Mansfield MD

Aaron S. Mansfield MD

Malignant pleural mesothelioma (MPM) is an inexorably progressive and almost universally fatal malignancy.1 The vast majority of cases are associated with exposure to fibrous minerals, specifically asbestos or erionite fibers. In addition, prior thoracic radiation therapy2 and germline loss of function BAP1 mutations3 have also been linked to the development of MPM. With the continued use of asbestos products in many countries, the incidence of MPM continues to rise worldwide, causing an estimated 43,000 deaths annually.4

Effective treatment options are largely lacking. The role of surgery and standard multimodality therapy remains controversial and may only benefit highly selected patients.5,6 Folate antimetabolite-based chemotherapy, the current standard of care, has modest benefits and has been shown to improve overall survival by approximately 3 months.7 Chemotherapy provides even less of a benefit for patients with sarcomatoid subtypes of MPM.8

Recently, immunotherapies have been shown to be effective for the treatment of metastatic melanoma and prostate cancer and are now approved by the Food and Drug Administration (FDA) for these diseases. In MPM, a number of isolated cases demonstrate that immune-mediated mechanisms can effectively target this tumor. Consequently, immunotherapeutic strategies are felt to represent an attractive alternative for the treatment of MPM. The complexity of the immune system allows for many ways to therapeutically modulate anti-tumor immunity. A comprehensive review of the immunologic therapies tested in MPM is beyond the scope this focused review, but can be found elsewhere.9

This review specifically focuses on the therapeutic modulation of immune checkpoints for the treatment of MPM. Despite the ability of the immune system to recognize tumors, effective anti-tumor immune responses are blunted by many immunosuppressive mechanisms.10 In addition to successful T-cell receptor and major histocompatibility complex binding (signal 1), effective T-cell activation against self, tumor, and foreign antigens also depends on activating costimulatory signals (signal 2), and the presence of effector cytokines (signal 3). Immune activation is controlled by negative costimulatory signals, immune checkpoints. Immune checkpoints are critical to maintain the delicate balance between effective antimicrobial responses, self-tolerance, and prevention of autoimmunity. The two most characterized immune checkpoints are the cytotoxic T-lymphocyte antigen-4 (CTLA-4) - CD80/CD86 (B7-1/B7-2) checkpoint, and programmed cell death 1 (PD-1) - programmed cell death ligand 1 (PD-L1, B7-H1) - programmed cell death ligand 2 (PD-L2, B7-DC). Both of these pathways have been implicated in tumor-mediated suppression of anti-tumor immunity.

CTLA-4 Inhibition

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