Background: Malignant pleural mesothelioma (MPM) is an incurable cancer predominantly induced by asbestos exposure. This aggressive tumour commonly presents at an advanced stage of disease. Although surgery, combination chemotherapy and radiotherapy may be used in disease management, median survival from diagnosis is less than 12 months. New therapeutic approaches are required to improve outcome in this disease.
Chimeric antigen receptors (CAR) are fusion molecules that couple the HLA- independent binding of a selected cell surface target antigen to the delivery of a tailored T-cell activating signal. Using CAR technology, we aim to develop a novel immunotherapy for MPM that is both safe and effective. These molecules are delivered to patient T-cells using retroviral gene-transfer, thereby stably re-directing their specificity for antigen. The receptor tyrosine kinase MET is overexpressed in >80% of MPM patients making it an attractive candidate for CAR directed immunotherapy.
Methods: Three second-generation cMet-targeted CARs (containing a fused CD28/CD3ζ endodomain) have been developed, distinguished by peptide-binding motifs. Functionality of MET-re targeted T-cells has been assessed by co-cultivation of genetically enhanced test and control T-cells with MPM cell lines that express MET at various levels.
Results: Studies to date have shown that human T-cells engineered to express cMet CARs can destroy mesothelioma tumour cell monolayers, accompanied by T-cell proliferation and cytokine production. To further potentiate the activity of the cMet targeted CARs, a dual targeting approach to both cMet and the ErbB family is currently under evaluation. The second advantage of this approach is in diminishing the potential toxicity risks associate with “on target, off tumour” toxicity. An MPM xenograft model has been established utilising bioluminescence to further evaluate functionality and toxicity in vivo.
Conclusions: These findings demonstrate proof of concept for the utility of CAR engineered T-cells to recognise and destroy cMet-expressing MPM tumour cells. We envisage that regional i.e. intrapleural delivery of human CAR positive T-cells could be used to maximise therapeutic index of this approach.
Citation Format: Thivyan Thayaparan, Sjoukje J.C. van der Stegen, Ana C. Parente Pereira Puri, Roseanna Maria Petrovic, James Spicer, John Maher. Immunotherapy of malignant pleural mesothelioma using cMET specific T-cells. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A075.