Cancer letters, 2017-05, Vol.393, p.52-59
2017
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- Autor(en) / Beteiligte
- Titel
- Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells
- Ist Teil von
- Cancer letters, 2017-05, Vol.393, p.52-59
- Ort / Verlag
- Ireland: Elsevier B.V
- Erscheinungsjahr
- 2017
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0304-3835eISSN: 1872-7980DOI: 10.1016/j.canlet.2017.02.015Titel-ID: cdi_proquest_miscellaneous_1881749019
- Format
- –
- Schlagworte
- Animals, Antigens, Cancer, Cell Line, Tumor, Chimeric antigen receptor, Clinical trials, Coculture Techniques, Cytokines, Epidermal growth factor receptor, ErbB Receptors - immunology, ErbB Receptors - metabolism, Genetic Therapy - methods, Hematology, Oncology and Palliative Medicine, Histology, Humans, Immunotherapy, Immunotherapy, Adoptive - methods, Interleukin-4 - immunology, Interleukin-4 - metabolism, Kinases, Laboratories, Lung cancer, Lung Neoplasms - genetics, Lung Neoplasms - immunology, Lung Neoplasms - metabolism, Lung Neoplasms - therapy, Lymphocytes, Tumor-Infiltrating - immunology, Lymphocytes, Tumor-Infiltrating - metabolism, Lymphocytes, Tumor-Infiltrating - transplantation, Medical prognosis, Mesothelioma, Mesothelioma - genetics, Mesothelioma - immunology, Mesothelioma - metabolism, Mesothelioma - therapy, Mesothelioma, Malignant, Mice, SCID, Multivariate analysis, Patients, Pleural Neoplasms - genetics, Pleural Neoplasms - immunology, Pleural Neoplasms - metabolism, Pleural Neoplasms - therapy, Receptor, ErbB-2 - metabolism, Receptor, ErbB-4 - metabolism, Receptors, Antigen, T-Cell - genetics, Receptors, Antigen, T-Cell - immunology, Receptors, Antigen, T-Cell - metabolism, Recombinant Fusion Proteins - metabolism, T-Lymphocytes - immunology, T-Lymphocytes - metabolism, T-Lymphocytes - transplantation, Time Factors, Transduction, Genetic, Tumor Burden, Tumors, Xenograft Model Antitumor Assays