Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells. (1st May 2017)

• Record Type: Journal Article
• Authors: Klampatsa, Astero; Achkova, Daniela Y.; Davies, David M.; Parente-Pereira, Ana C.; Woodman, Natalie; Rosekilly, James; Osborne, Georgina; Thayaparan, Thivyan; Bille, Andrea; Sheaf, Michael; Spicer, James F.; King, Juliet; Maher, John
• Is Part Of: Cancer letters. Volume 393(2017)
• Page Start: 52
• Page End: 59
• Publication Date: 2017-05-01
• Subjects: Lung cancer -- Mesothelioma -- Chimeric antigen receptor -- Epidermal growth factor receptor; BLI bioluminescence imaging -- CAR chimeric antigen receptor -- EGFR epidermal growth factor receptor -- ffLuc firefly luciferase -- IL interleukin -- i.p. intraperitoneal -- MPM malignant pleural mesothelioma -- PSMA prostate-specific membrane antigen -- p/s photons per second -- RFP red fluorescence protein -- UT untransduced; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.02.015
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4 + T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma. Highlights: Mesotheliomas express EGF receptor in 80% and ErbB4 in 50% of cases. T-cells from mesothelioma patients are amenable to efficient genetic engineering. ErbB-targeted patient CAR T-cells mediate potent activity against mesothelioma. Tumor regression is not accompanied by toxicity. Clinical evaluation of this approach is warranted.