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

Gut - Tập 68 Số 6 - Trang 1052-1064 - 2019
Deepak B. Thimiri Govinda Raj1, Ming-Hsin Yang1, David T. Rodgers2, Eric Hampton2, Julfa Begum1, A. F. Mustafa3, Daniela Lorizio1, Irene Garces1, David Propper4, James G. Kench5, Hemant M. Kocher6, Travis S. Young7, Alexandra Aicher1, Christopher Heeschen8
1Stem Cells in Cancer and Ageing, Barts Cancer Institute (BCI), Queen Mary University of London, London, UK
2Biologics, California Institute for Biomedical Research, La Jolla, California, USA
3Biological Service Unit, Barts Cancer Institute, London, UK
4Cancer and Inflammation, Barts Cancer Institute, London, UK
5Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
6Director of the Barts Pancreatic Cancer Tissue Bank, Barts Cancer Institute (BCI), Queen Mary University of London, London, UK
7California Institute for Biomedical Research, USA
8School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia

Tóm tắt

ObjectivePancreatic 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.DesignIn 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.ResultsSwitchable 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.ConclusionThese 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.

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Gut

Tập 68 Số 6

1052-1064

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