Article Text
Abstract
Objective Pancreatic ductal adenocarcinoma (PDAC) is a disease of unmet medical need. While immunotherapy with chimeric antigen receptor T (CAR-T) cells has shown much promise in haematological malignancies, their efficacy for solid tumours is challenged by the lack of tumour-specific antigens required to avoid on-target, off-tumour effects. Switchable CAR-T cells whereby activity of the CAR-T cell is controlled by dosage of a tumour antigen-specific recombinant Fab-based ‘switch’ to afford a fully tunable response may overcome this translational barrier.
Design In this present study, we have used conventional and switchable CAR-T cells to target the antigen HER2, which is upregulated on tumour cells, but also present at low levels on normal human tissue. We used patient-derived xenograft models derived from patients with stage IV PDAC that mimic the most aggressive features of PDAC, including severe liver and lung metastases.
Results Switchable CAR-T cells followed by administration of the switch directed against human epidermal growth factor receptor 2 (HER2)-induced complete remission in difficult-to-treat, patient-derived advanced pancreatic tumour models. Switchable HER2 CAR-T cells were as effective as conventional HER2 CAR-T cells in vivo testing a range of different CAR-T cell doses.
Conclusion These results suggest that a switchable CAR-T system is efficacious against aggressive and disseminated tumours derived from patients with advanced PDAC while affording the potential safety of a control switch.
- pancreatic cancer
- stem cells
- immunotherapy
- liver metastases
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Footnotes
Contributors DR developed the study concept, acquired, analysed and interpreted data as well as drafted and wrote the manuscript; M-HY, DaR, ENH, JB, DL and IG acquired and analysed data; AM helped with the in vivo experiments; DP and HMK collected samples from patients with pancreatic cancer; JGK analysed histological samples; TSY, AA and CH developed the study concept, obtained funding, interpreted the data and wrote the manuscript.
Funding Research was supported by the ERC Advanced Investigator Grant (Pa-CSC 233460 to CH) and the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 602783 (CAM-PaC to CH), UNSW SHARP Seed Funding (to CH), Pancreatic Cancer UK under the grant agreements RIF2014_CH, RIF2015_CH (to CH) and RIF2015_AA (to AA) , American Cancer Society (RSG-16-200-01-LIB to TSY) and Cancer Research UK Centre Grant to BCI (C16420/A18066). Barts Pancreatic Tissue Bank (BPTB) is funded by the Pancreatic Cancer Research Fund.
Competing interests None declared.
Ethics approval All experiments were approved by the Animal Experimental Ethics Committee (Home Office Project License PPL 70/8129) and performed in accordance with the guidelines for Ethical Conduct in the Care and Use of Animals.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement There are no additional unpublished data from this study.
Correction notice This article has been corrected since it published Online First. An additional author has been added and the acknowledgements, contributors and funding statements updated.