CAR T-cell immunotherapy of MET-expressing malignant mesothelioma.

Autor:	Thayaparan T; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Petrovic RM; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Achkova DY; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Zabinski T; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Davies DM; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Klampatsa A; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.; Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Parente-Pereira AC; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Whilding LM; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., van der Stegen SJ; The Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA., Woodman N; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK., Sheaff M; Department of Histopathology, Barts Health NHS Trust, The Royal London Hospital, London E1 2ES, UK., Cochran JR; Department of Bioengineering and Chemical Engineering, Stanford Cancer Institute, 443 Via Ortega, Room 356, Stanford, CA, USA., Spicer JF; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.; Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK., Maher J; King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.; Department of Clinical Immunology and Allergy, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK.; Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex, BN21 2UD, UK.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2017 Aug 14; Vol. 6 (12), pp. e1363137. Date of Electronic Publication: 2017 Aug 14 (Print Publication: 2017).
DOI:	10.1080/2162402X.2017.1363137
Abstrakt:	Mesothelioma is an incurable cancer for which effective therapies are required. Aberrant MET expression is prevalent in mesothelioma, although targeting using small molecule-based therapeutics has proven disappointing. Chimeric antigen receptors (CARs) couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. Here, we evaluated the anti-tumor activity of MET re-targeted CAR T-cells against mesothelioma. Using immunohistochemistry, MET was detected in 67% of malignant pleural mesotheliomas, most frequently of epithelioid or biphasic subtype. The presence of MET did not influence patient survival. Candidate MET-specific CARs were engineered in which a CD28+CD3ζ endodomain was fused to one of 3 peptides derived from the N and K1 domains of hepatocyte growth factor (HGF), which represents the minimum MET binding element present in this growth factor. Using an NIH3T3-based artificial antigen-presenting cell system, we found that all 3 candidate CARs demonstrated high specificity for MET. By contrast, these CARs did not mediate T-cell activation upon engagement of other HGF binding partners, namely CD44v6 or heparan sulfate proteoglycans, including Syndecan-1. NK1-targeted CARs demonstrated broadly similar in vitro potency, indicated by destruction of MET-expressing mesothelioma cell lines, accompanied by cytokine release. In vivo anti-tumor activity was demonstrated following intraperitoneal delivery to mice with an established mesothelioma xenograft. Progressive tumor regression occurred without weight loss or other clinical indicators of toxicity. These data confirm the frequent expression of MET in malignant pleural mesothelioma and demonstrate that this can be targeted effectively and safely using a CAR T-cell immunotherapeutic strategy.
Databáze:	MEDLINE
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