Solomon, Isabelle;
(2020)
Targeting regulatory T cells for therapeutic gain in cancer therapy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Regulatory T cell (Treg) abundance associates with diminished anti-tumour immunity and poor prognosis in human epithelial cancers, underscoring their value as an immunotherapy target. There has been limited clinical success in targeting this cell population likely due to a lack of consensus on the most selective targets for depletion of Treg cells, and the limited mechanistic insight into the activity of these antibodies in vivo. Recent work from our lab (Vargas et al., 2017) demonstrates that CD25 (the high affinity alpha receptor subunit for IL-2) is a selective target for the depletion of regulatory T cells in mouse and human malignancies. However, despite being a selective target, aCD25PC61 lacks single agent activity against tumours. Based on this, two projects were developed, both focusing on CD25 as a target for Treg depletion. The first project focused on the development of a bispecific antibody targeting both CD25 and PD-L1, with the rationale being that Treg depletion would be targeted to the tumour (due to PD-L1 upregulation in the tumour microenvironment). The bispecific antibody was developed in the lab, and its production, characterisation and activity in vitro and in vivo is discussed in depth in Chapter 4. The second project was initiated as a hypothesis that the in vivo activity of available anti-CD25 mAbs targeting human and mouse Treg cells, is likely limited by their IL-2 blocking activity. By developing a CD25 antibody which does not block IL-2 signalling, this hypothesis was tested in vivo in various mouse tumour models. The work presented in this thesis demonstrates the critical importance of endogenous IL-2 to the function of the CD4 and CD8 effector compartments in the context of Treg depletion and that this is key for the superior anti-tumour activity of aCD25NIB.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Targeting regulatory T cells for therapeutic gain in cancer therapy |
| 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/10094239 |
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