Background: Malignant pleural mesothelioma (MPM) is an incurable cancer predominantly induced by asbestos exposure. This aggressive tumor 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 MET-targeted peptide-binding motifs have been incorporated into a second generation CAR framework containing a fused CD28/CD3ζ endodomain. Functional assessment of MET-targeted CARs 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: In preliminary studies we have shown that human T-cells engineered to express MET CARs can destroy mesothelioma tumor cell monolayers, accompanied by T-cell proliferation and cytokine production. Xenograft models are currently under development using 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 MET-expressing MPM tumor 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 v.d Stegen, Ana C. Parente Pereira, Roseanna Petrovic, James Spicer, John Maher. Immunotherapy of malignant pleural mesothelioma using MET specific t – cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2800. doi:10.1158/1538-7445.AM2014-2800