Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells.
View/ Open
Date
2017-05-01ICR Author
Author
Klampatsa, A
Achkova, DY
Davies, DM
Parente-Pereira, AC
Woodman, N
Rosekilly, J
Osborne, G
Thayaparan, T
Bille, A
Sheaf, M
Spicer, JF
King, J
Maher, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
T-Lymphocytes
Lymphocytes, Tumor-Infiltrating
Cell Line, Tumor
Animals
Humans
Mice, SCID
Mesothelioma
Lung Neoplasms
Pleural Neoplasms
Receptor, erbB-2
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
Interleukin-4
Immunotherapy, Adoptive
Tumor Burden
Coculture Techniques
Xenograft Model Antitumor Assays
Transduction, Genetic
Time Factors
Genetic Therapy
Receptor, ErbB-4
ErbB Receptors
Mesothelioma, Malignant
Research team
Thoracic Oncology Immunotherapy Group (TOIG)
Language
eng
Date accepted
2017-02-10
License start date
2017-05
Citation
Cancer letters, 2017, 393 pp. 52 - 59
Publisher
ELSEVIER IRELAND LTD