Malignant pleural mesothelioma (MPM) is a rare but aggressive cancer that arises from the mesothelial cells lining the pleura, which is the thin layer of tissue that covers the lungs and chest wall. MPM is primarily caused by exposure to asbestos fibers, and it is associated with a poor prognosis due to the late diagnosis and limited treatment options. However, recent advances in the understanding of the molecular mechanisms underlying MPM and the development of novel therapeutic strategies have shown promising results in improving the survival and quality of life of MPM patients. In this answer, we will discuss the most promising new treatments for MPM, including immunotherapy, targeted therapy, and gene therapy.
Immunotherapy: Immunotherapy is a new approach to cancer treatment that harnesses the patient’s immune system to fight cancer cells. Several immunotherapeutic agents are currently being investigated for the treatment of MPM, including checkpoint inhibitors, CAR-T cell therapy, and cancer vaccines.
Checkpoint inhibitors: Checkpoint inhibitors are monoclonal antibodies that block the interaction between inhibitory receptors on T cells and their ligands on cancer cells, thereby allowing the immune system to recognize and attack cancer cells. The most studied checkpoint inhibitors in MPM are pembrolizumab and nivolumab, which target the PD-1 receptor, and ipilimumab, which targets the CTLA-4 receptor. Clinical trials have shown that checkpoint inhibitors can induce objective responses and improve survival in a subset of MPM patients, especially those with high PD-L1 expression or a non-epithelioid subtype. However, the response rate to checkpoint inhibitors is still low, and biomarkers to predict response are needed.
CAR-T cell therapy: CAR-T cell therapy is a type of adoptive cell therapy that involves genetically modifying T cells to express chimeric antigen receptors (CARs) that can recognize and kill cancer cells. CAR-T cell therapy has shown remarkable success in the treatment of hematological malignancies, but its efficacy in solid tumors, including MPM, is still limited. Several clinical trials are underway to evaluate the safety and efficacy of CAR-T cell therapy in MPM, targeting different antigens such as mesothelin, B7-H3, and CD47.
Cancer vaccines: Cancer vaccines are designed to stimulate the immune system to recognize and attack cancer cells by presenting cancer-specific antigens. Several types of cancer vaccines, including peptide vaccines, dendritic cell vaccines, and whole-cell vaccines, are being investigated for the treatment of MPM. The most advanced cancer vaccine in MPM is CRS-207, a live-attenuated Listeria monocytogenes vaccine that expresses mesothelin, which is overexpressed in most MPM tumors. Clinical trials have shown that CRS-207 can induce immune responses and improve survival in combination with chemotherapy, although its efficacy as a monotherapy is limited.
Targeted therapy: Targeted therapy is a type of cancer treatment that specifically targets molecules or pathways that are essential for cancer cell survival and growth, while sparing normal cells. Several targeted therapies are being developed for the treatment of MPM, focusing on different molecular targets such as receptor tyrosine kinases, angiogenesis, and epigenetic regulators.
Receptor tyrosine kinase inhibitors: Receptor tyrosine kinases (RTKs) are cell surface receptors that regulate cell growth, survival, and differentiation. Several RTK inhibitors, such as crizotinib, cabozantinib, and vandetanib, are being evaluated for the treatment of MPM, targeting different receptors such as MET, VEGFR, and EGFR. Clinical trials have shown that RTK inhibitors can induce objective responses and improve progression-free survival in a subset of MPM patients, especially those with MET exon 14 skipping mutations or MET amplification. However, the response rate to RTK inhibitors is still modest, and resistance mechanisms need to be overcome.
Angiogenesis inhibitors: Angiogenesis is the process of forming new blood vessels, which is essential for tumor growth and metastasis. Several angiogenesis inhibitors, such as bevacizumab, nintedanib, and sorafenib, are being investigated for the treatment of MPM, targeting different angiogenic factors such as VEGF, PDGF, and FGFR. Clinical trials have shown that angiogenesis inhibitors can improve progression-free survival and overall survival in combination with chemotherapy, although their efficacy as a monotherapy is limited.
Epigenetic inhibitors: Epigenetics refers to the regulation of gene expression by modifications of DNA and histones, which can be altered in cancer cells. Several epigenetic inhibitors, such as histone deacetylase inhibitors (HDACi), DNA methyltransferase inhibitors (DNMTi), and bromodomain and extra-terminal inhibitors (BETi), are being developed for the treatment of MPM. Clinical trials have shown that HDACi can induce objective responses and improve survival in combination with chemotherapy, although their efficacy as a monotherapy is limited. DNMTi and BETi are still in early-phase clinical trials.
Gene therapy: Gene therapy is a type of treatment that involves the delivery of genetic material into cells to correct or replace defective genes or to enhance the immune response against cancer cells. Several gene therapy approaches are being investigated for the treatment of MPM, including oncolytic viruses, gene transfer vectors, and gene editing.
Oncolytic viruses: Oncolytic viruses are viruses that can selectively infect and kill cancer cells while sparing normal cells. Several oncolytic viruses, such as adenoviruses, herpes simplex viruses, and measles viruses, are being developed for the treatment of MPM. Clinical trials have shown that oncolytic viruses can induce objective responses and improve survival in a subset of MPM patients, especially those with a non-epithelioid subtype. However, the response rate to oncolytic viruses is still low, and safety concerns need to be addressed.
Gene transfer vectors: Gene transfer vectors are vehicles that can deliver therapeutic genes into cells to correct or replace defective genes. Several gene transfer vectors, such as retroviruses, lentiviruses, and adenoviruses, are being investigated for the treatment of MPM. The most advanced gene transfer vector in MPM is TR002, a retroviral vector that delivers a tumor suppressor gene called ING4, which is frequently deleted or downregulated in MPM tumors. Clinical trials have shown that TR002 can induce objective responses and improve survival in a subset of MPM patients, especially those with a non-epithelioid subtype. However, the response rate to TR002 is still modest, and safety concerns need to be addressed.
Gene editing: Gene editing is a type of gene therapy that involves the precise modification of DNA sequences using engineered nucleases, such as CRISPR-Cas9. Several gene editing approaches, such as knockout of oncogenes or insertion of tumor suppressor genes, are being developed for the treatment of MPM. However, gene editing is still in the early stages of development, and its safety and efficacy in humans need to be further evaluated.
In conclusion, MPM is a challenging cancer to treat, but recent advances in the understanding of its molecular mechanisms and the development of novel therapeutic strategies have shown promising results in improving the survival and quality of life of MPM patients. Immunotherapy, targeted therapy, and gene therapy are the most promising new treatments for MPM, and they are being evaluated in clinical trials to determine their safety and efficacy. Further research is needed to identify biomarkers to predict response and resistance mechanisms to overcome, and to optimize the combination of different therapeutic approaches.
