Breaking Through the Treatment Desert of CAR-T Cell Therapy for Malignant Mesothelioma

ByHolly Zink
Breaking Through the Treatment Desert of CAR-T Cell Therapy for Malignant Mesothelioma

Malignant mesothelioma is a rare and aggressive cancer caused by asbestos exposure. Treatment options are limited. This is especially true for elderly patients. They may struggle with conventional therapies due to their age and other health problems.

Chimeric antigen receptor (CAR)-T cell therapy has shown promise in treating various cancers, including malignant mesothelioma. CAR-T cell therapy works by targeting tumor-specific antigens. However, the journey has been fraught with challenges, particularly concerning the mesothelin (MSLN) antigen.

A new article explores the latest advancements in CAR-T cell therapy for malignant mesothelioma and what the future holds for patients.

The Challenge of Mesothelin-Targeted CAR-T Cells

MSLN is a popular tumor antigen for mesothelioma. Initial trials with MSLN-targeted CAR-T cells showed low effectiveness but were safe. However, recent reports are troubling. For example, one study found high MSLN-directed CAR-T cell activity led to severe lung issues. This has sparked safety concerns. It’s clear we need new targets and strategies to improve the safety and effectiveness of CAR-T therapies for mesothelioma.

Researchers are looking for new targets beyond MSLN. They are exploring FAP, pan-ErbB receptors (EGFR and HER2), and CSPG4. These show promise in preclinical studies. A recent study focused on a new target, HEG1, for CAR-T cell therapy. This therapy was tested in models of malignant mesothelioma, showing good results.

Moreover, the specific epitopes of MSLN targeted by CAR-T cells can significantly impact their efficacy. CAR-T cells targeting membrane-proximal epitopes have shown enhanced tumor infiltration and persistence. For instance, h15B6 CAR-T cells target a juxtamembrane epitope of MSLN. They caused complete regression in preclinical models, outdoing traditional CAR-T cells. The traditional cells target more distal epitopes.

Combining Therapies for Enhanced Efficacy

Pairing CAR-T cell therapy with other treatments shows promise for treating solid tumors, such as malignant mesothelioma. One approach is to modify CAR-T cells. This modification adds proteins like PD-1 antibodies or interleukin-15 (IL-15) to boost their function. Another method is to use CAR-T cells with existing drugs, such as pembrolizumab, a PD-1 inhibitor. Early trials have been successful.

These strategies aim to increase CAR-T cell survival and their ability to fight tumors. They target the complex and varied tumor microenvironment (TME), which often leads to tumor regrowth and limits the effectiveness of treatments on solid tumors.

Future Directions and Considerations

Researchers are enhancing CAR-T cell therapies. They look for new targets and better combos. These therapies have great potential. But, they can cause severe side effects. This is especially true for highly active CAR-T cells.

Current studies aim to find the safest, most effective targets, and modifications. Recent progress includes using genetic knockouts. These help CAR-T cells fight exhaustion and improve their cancer-fighting abilities. Targets like SUV39H1 and DNMT3A are promising. They boost CAR-T cells against solid tumors.

Scientists are also exploring PROTACs. These technologies could make CAR-T cell therapies even better.

Developing CAR-T cell therapy for mesothelioma in elderly patients is tough, but it shows promise. New targets, optimized epitopes, and combined strategies improve treatments. Safety is a concern. Yet, research and trials are advancing, aiming for better outcomes. For the elderly and their caregivers, staying updated is key. These advancements could change mesothelioma treatment.

Source:

Wang, Yuning, Guo Zhao, Shujun Xing, Shuhang Wang, and Ning Li. “Breaking through the Treatment Desert of Conventional Mesothelin-Targeted CAR-T Cell Therapy for Malignant Mesothelioma: A Glimpse into the Future.” Pharmacological Research 204 (June 1, 2024): 107220. https://doi.org/10.1016/j.phrs.2024.107220.

Similar Posts

  • | |

    Doctors Describe "Concrete Therapeutic Approach" for Mesothelioma

    ByAlex Strauss

    A team of medical researchers in Italy have achieved what they are calling “excellent” tumor control and survival results in malignant pleural mesothelioma patients using a combination of surgery, chemotherapy, and radiotherapy. Caused by exposure to asbestos, mesothelioma typically spreads quickly across the lung-encasing membrane called the pleura. There is no known cure but treatments are improving. In the current prospective study, 20 malignant pleural mesothelioma patients underwent radical pleurectomy/decortication followed by high doses of radiation. After surgeons removed as much of the visible mesothelioma tumor and surrounding tissue as possible, patients received 50Gy of radiation to the effected side of their chest, delivered in 25 fractions. Regions of particular concern for mesothelioma regrowth got an extra radiation “boost” to…

  • | |

    Does Radiotherapy Reduce Mesothelioma Pain?

    ByAlex Strauss

    A new study says there is not enough evidence to support the use of radiotherapy for the treatment of pain associated with malignant pleural mesothelioma. Researchers at the University of Edinburgh in Scotland reviewed a range of past studies on mesothelioma pain and radiotherapy by searching databases that date back as far as 1974. To be eligible to be included in their review, the study had to focus on malignant pleural mesothelioma and radiotherapy given “with the intent of improving pain”. The study also had to report doses and fractionation of the radiotherapy and how the pain responded. In all, the researchers found eight studies on mesothelioma pain and radiotherapy that met the criteria. Two of the studies were prospective…

  • | |

    Radiotherapy for Mesothelioma: Better But Still Limited

    ByAlex Strauss

    A form of highly-targeted radiation therapy for mesothelioma is better than it used to be, but is still risky. That is the message of a recent article on intensity-modulated radiation therapy (IMRT) in Seminars in Thoracic and Cardiovascular Surgery. Author Kenneth E. Rosenzweig, MD, a Radiation Oncologist with Mount Sinai Hospital in New York, reviewed recent studies on IMRT and mesothelioma. He concludes that, while the “troubling toxicity” associated with IMRT when it was first introduced has not been entirely eliminated, the fact that clinicians now have more experience with it is making a positive difference for mesothelioma patients. Before targeted therapies like IMRT were available, high-dose radiation was not usually a feasible option for mesothelioma since the irregular shape…

  • | |

    A Second-Line Option for Mesothelioma?

    ByAlex Strauss

    Although survival was not significantly extended, the chemotherapy drug vinorelbine might be a treatment option for mesothelioma patients whose cancer has returned after first-line chemotherapy with pemetrexed. A new study on vinorelbine as a second-line treatment finds that the drug is “moderately active” in mesothelioma patients who were initially treated with pemetrexed-based chemotherapy. Pemetrexed (Alimta), along with a platinum-based drug like cisplatin, is the primary first-line drug therapy for mesothelioma. But vinorelbine is gaining attention as a possible option for mesothelioma, in part because it is available in a less expensive generic form. In “Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma”, the Italian authors detail the results of their study on 59 patients with unresectable pleural mesothelioma.  These patients…

  • | |

    Repeat HIPEC Improves Mesothelioma Survival

    ByAlex Strauss

    If one cytoreductive surgery and HIPEC procedure for mesothelioma is good, subsequent treatments may be even better. That is the central message of research conducted at the Moffitt Cancer Center in Florida. The study’s aim was to assess overall survival among peritoneal mesothelioma patients who had not just one, but two or more rounds of heated intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery. The cytoreduction/HIPEC approach has become popular for peritoneal mesothelioma, a treatment-resistant cancer of abdominal membranes caused by asbestos. Cytoreductive surgery involves removing as much of the mesothelioma tumor as possible from the abdomen. Because the shape and spreading pattern of mesothelioma tumors make complete cytoreduction difficult, the surgery is often followed by a rinse with a heated solution…

  • | |

    Value of Mesothelioma Surgery Challenged for Healthy Patients

    ByAlex Strauss

    New research conducted in Italy and presented at the 15th World Conference on Lung Cancer in Sydney, Australia suggests that mesothelioma surgery – no matter what kind – may not offer a survival advantage over medical management for the healthiest of patients. Mesothelioma is a rare but aggressive malignancy that is highly resistant to standard cancer treatments. The two types of mesothelioma surgery considered to be options for people with resectable cancer are pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP). While EPP is more radical than P/D because it involves removing a lung, both carry a heavy risk of complications and, according to the Italian researchers, may not be of value for certain patients. The study reviewed data from 1,365…