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Gut. 2018 Aug 18. pii: gutjnl-2018-316595. doi: 10.1136/gutjnl-2018-316595. [Epub ahead of print]

Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma.

Author information

1
Stem Cells in Cancer and Ageing, Barts Cancer Institute (BCI), Queen Mary University of London, London, UK.
2
Biologics, California Institute for Biomedical Research, La Jolla, California, USA.
3
Biological Service Unit, Barts Cancer Institute, London, UK.
4
Cancer and Inflammation, Barts Cancer Institute, London, UK.
5
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
6
School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.

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.

KEYWORDS:

immunotherapy; liver metastases; pancreatic cancer; stem cells

PMID:
30121627
DOI:
10.1136/gutjnl-2018-316595
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