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

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.


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.

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