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Journal of Translational Medicine

, 11:187

Immunobiology and immunotherapy

Abstract

IntroductionMalignant pleural mesothelioma MPM is an incurable malignant disease, which results from chronic exposition to asbestos in at least 70% of the cases. Fibroblast activation protein FAP is predominantly expressed on the surface of reactive tumor-associated fibroblasts as well as on particular cancer types. Because of its expression on the cell surface, FAP is an attractive target for adoptive T cell therapy. T cells can be re-directed by retroviral transfer of chimeric antigen receptors CAR against tumor-associated antigens TAA and therefore represent a therapeutic strategy of adoptive immunotherapy.

MethodsTo evaluate FAP expression immunohistochemistry was performed in tumor tissue from MPM patients. CD8 human T cells were retrovirally transduced with an anti-FAP-F19-∆CD28-CD3ζ-CAR. T cell function was evaluated in vitro by cytokine release and cytotoxicity assays. In vivo function was tested with an intraperitoneal xenograft tumor model in immunodeficient mice.

ResultsFAP was found to be expressed in all subtypes of MPM. Additionally, FAP expression was evaluated in healthy adult tissue samples and was only detected in specific areas in the pancreas, the placenta and very weakly for cervix and uterus. Expression of the anti-FAP-F19-∆CD28-CD3ζ-CAR in CD8 T cells resulted in antigen-specific IFNγ release. Additionally, FAP-specific re-directed T cells lysed FAP positive mesothelioma cells and inflammatory fibroblasts in an antigen-specific manner in vitro. Furthermore, FAP-specific re-directed T cells inhibited the growth of FAP positive human tumor cells in the peritoneal cavity of mice and significantly prolonged survival of mice.

ConclusionFAP re-directed CD8 T cells showed antigen-specific functionality in vitro and in vivo. Furthermore, FAP expression was verified in all MPM histotypes. Therefore, our data support performing a phase I clinical trial in which MPM patients are treated with adoptively transferred FAP-specific re-directed T cells.

Electronic supplementary materialThe online version of this article doi:10.1186-1479-5876-11-187 contains supplementary material, which is available to authorized users.

Christoph Renner and Ulf Petrausch contributed equally to this work.

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Autor: Petra C Schuberth - Christian Hagedorn - Shawn M Jensen - Pratiksha Gulati - Maries van den Broek - Axel Mischo - Alex So

Fuente: https://link.springer.com/







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