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ROR1-targeted adoptive immunotherapies

Harrasser, Micaela; (2020) ROR1-targeted adoptive immunotherapies. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The tumour antigen ROR1 plays a critical role in tumorigenesis and is overexpressed in several haematological and solid malignancies including triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Its absence on most of healthy tissues makes it an attractive target for cancer immunotherapy. Cancer immunotherapy has opened a new era of cancer treatments. Successful examples include therapeutic antibodies (e.g. Rituximab, and immune checkpoint inhibitors) and adoptive cell therapy with engineered T cells expressing a Chimeric Antigen Receptor (CAR), particularly against haematological malignancies. CAR-T cells have so far had limited success against solid tumours. Overexpression of inhibitory receptor ligands such as PD-L1 by tumour cells is one of the main mechanisms that makes the anti-tumour immune response ineffective. We developed a second generation ROR1-41BB-CD3ζ CAR targeting ROR1. These CAR-T cells rapidly acquired a phenotype associated with increased expression of programmed death receptor 1 (PD-1) following exposure to ROR1-expressing tumour targets. To bolsters potency, we engineered the lentiviral CAR construct to enable IL-2 mediated, NFAT-induced secretion of anti-PD-1 single-chain variable fragments (scFv) within the tumour environment following CAR T-cell activation. Local secretion of anti-PD1 scFv led to increased anti-tumour activity against TNBC and NSCLC tumour cell lines in in vitro co-culture studies. In a murine xenograft model of TNBC, tumour growth was significantly decreased and associated with a significant survival benefit compared to parental ROR1 CAR-T cells and to combination therapy with ROR1 CAR-T cells and anti-PD1 monoclonal antibody. Thus, second-generation CAR T cells engineered to secrete anti-PD-1 scFv shows promise and represents a clinically relevant approach to improving potency of CAR-T cells against solid tumours whilst limiting toxicities associated with systemic administration of monoclonal antibody-mediated checkpoint inhibition.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: ROR1-targeted adoptive immunotherapies
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10092674
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