Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells.
BACKGROUND
Malignant 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.


METHODS
To 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.


RESULTS
FAP 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.


CONCLUSIONS
FAP 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.
Department of Oncology, University Hospital Zurich, Rämistr. 100, 8091 Zürich, Switzerland.
Petra C
PC
Schuberth
Christian
C
Hagedorn
Shawn M
SM
Jensen
Pratiksha
P
Gulati
Maries
M
van den Broek
Axel
A
Mischo
Alex
A
Soltermann
Astrid
A
Jüngel
Osiris
O
Marroquin Belaunzaran
Rolf
R
Stahel
Christoph
C
Renner
Ulf
U
Petrausch
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D010450:Endopeptidases; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology* / Q000628:therapy*; D008565:Membrane Proteins / Q000378:metabolism*; D008654:Mesothelioma / Q000276:immunology* / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D010537:Peritoneum / Q000473:pathology; D010997:Pleural Neoplasms / Q000276:immunology* / Q000628:therapy*; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays; D000099167:Fibroblast Activation Protein Alpha
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha