New Era for Malignant Pleural Mesothelioma: Updates on Therapeutic Options

Abstract

Malignant pleural mesothelioma (MPM) is a rare malignancy with few treatment options. Recent advances have led to US Food and Drug Administration approvals and changes in the standard of care with a novel biomedical device approved for use with platinum-pemetrexed, and also for immunotherapy agents to be included as a frontline treatment option in unresectable disease. Although predictive biomarkers for systemic therapy are not currently in use in clinical practice, it is essential to correctly identify the MPM histology to determine an optimal treatment plan. Patients with nonepithelioid MPM may have a greater magnitude of benefit to dual immunotherapy checkpoint inhibitors and this regimen should be preferred in the frontline setting for these patients. However, all patients with MPM can derive benefit from immunotherapy treatments, and these agents should ultimately be used at some point during their treatment journey. There are ongoing studies in the frontline unresectable setting that may further define the frontline therapy space, but a critical area of research will need to focus on the immunotherapy refractory population. This review article will describe the new developments in the areas of biology with genomics and chromothripsis, and also focus on updates in treatment strategies in radiology, surgery, radiation, and medical oncology with cellular therapies. These recent innovations are generating momentum to find better therapies for this disease.

FIG 1.

Chromothripsis and common alterations in mesothelioma. (A) When both copy-number alterations and mutations are considered, NF2, BAP1, and CDKN2A are the most frequently altered genes according to The Cancer Genome Atlas analysis (TCGA). Copy-number losses or deletions are more common than single-nucleotide mutations for most of these genes, likely because of underlying structural variants. This circular barplot was created with the R package circlize. The percentages of alterations are slightly higher than summarized in the TCGA report since we included both copy-number alterations and mutations regardless of whether the genes were fully inactivated. (B) Sometimes these structural variants are consistent with a pattern of chromothripsis, which likely results from the disordered reassembly of a shattered chromosome. This circos plot represents a pleural mesothelioma specimen from a prior publication. Copy number is presented as a normalized read depth (NRD) calculated in reference to the diploid level (yellow line, NRD = 2). Regions of the genome calculated to be within the normal diploid level are colored gray, regions of gain are colored blue, and regions of loss are colored red. Dashed lines are provided at increments of NRD = 1 with an upper boundary of NRD = 6. Breakpoint junctions are presented as magenta lines connecting two breakpoints. This circos diagram was made by James Smadbeck, PhD, at Mayo Clinic with a custom R package.

FIG 2.

Right-sided hemithoracic intensity-modulated pleural radiation therapy plan to a total dose of 5,040 cGy in 28 fractions. The red line represents the planning target volume.

FIG 3.

Examples of cellular therapies. (A) In most clinical trials with dendritic cell vaccines, monocytes are removed by leukapheresis and matured, then loaded with tumor lysates or peptides, and administered to patients. (B) Similarly, to construct CAR-T cells, lymphocytes are isolated after leukapheresis and then undergo DNA or RNA transfection, or viral transduction, of a chimeric antigen receptor against a specific antigen, and are then administered. While the CAR-T cells are being created, patients typically undergo lymphodepletion to reduce immunosuppressive regulatory T cells. CAR-T, chimeric antigen receptor T cells; DC, dendritic cell. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.