Clinical cancer research, 2011-07, Vol.17 (14), p.4719-4730
2011
Details
- Autor(en) / Beteiligte
- Titel
- Expression of a Functional CCR2 Receptor Enhances Tumor Localization and Tumor Eradication by Retargeted Human T cells Expressing a Mesothelin-Specific Chimeric Antibody Receptor
- Ist Teil von
- Clinical cancer research, 2011-07, Vol.17 (14), p.4719-4730
- Ort / Verlag
- Philadelphia, PA: American Association for Cancer Research
- Erscheinungsjahr
- 2011
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.CCR-11-0351Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3612507
- Format
- –
- Schlagworte
- 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