Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T cells Expressing a Mesothelin-Specific Chimeric Antibody Receptor

• Published in: Clinical cancer research 2011-07, Vol.17 (14), p.4719-4730
• Main Authors: MOON, Edmund K, CARPENITO, Carmine, JING SUN, WANG, Liang-Chuan S, KAPOOR, Veena, PREDINA, Jarrod, POWELL, Daniel J, RILEY, James L, JUNE, Carl H, ALBELDA, Steven M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Movement - genetics; Cell Movement - immunology; Chemokines - biosynthesis; Cytotoxicity, Immunologic - immunology; Gene Expression Regulation, Neoplastic; GPI-Linked Proteins - immunology; Humans; Lymphocyte Activation - immunology; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Medical sciences; Mesothelioma - genetics; Mesothelioma - immunology; Mesothelioma - metabolism; Mice; Mice, Inbred NOD; Mice, Knockout; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Pharmacology. Drug treatments; Pleural Neoplasms - genetics; Pleural Neoplasms - immunology; Pleural Neoplasms - metabolism; Receptors, CCR2 - genetics; Receptors, CCR2 - immunology; Receptors, CCR2 - metabolism; Receptors, Chemokine - immunology; Receptors, Chemokine - metabolism; Single-Chain Antibodies - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transduction, Genetic
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-0351

Adoptive T-cell immunotherapy with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors to adequately exert therapeutic effects. The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM; a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector, and the modified T cells were used to treat established mesothelin-expressing tumors. CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T-cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T-cell tumor infiltration by day 5 compared with mesoCAR T cells. This was associated with significantly increased antitumor activity. CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve antitumor efficacy in vivo.