Regulatory T cell therapies for immune modulation—translating mechanistic insights to next-generation products

Thesis

Regulatory T cells (Tregs) are critical mediators of immune homeostasis controlling both the initiation and amplitude of effector responses towards non-self tissue whilst maintaining tolerance of self tissues. They possess multiple non-redundant immunosuppressive mechanisms including the ability to confer regulatory capacity to non-Treg cells in a process termed infectious tolerance; the prospect of therapeutically harnessing these properties to control the aberrant immune responses that characterise autoimmune diseases and transplant rejection is alluring. In recent decades, adoptive transfer of autologous Treg as a so-called ‘living drug’ or cell therapy has emerged as a promising therapeutic strategy. Pioneered in Oxford, Treg cell therapy is currently under evaluation to enable minimisation of conventional immunosuppression following kidney transplantation in the world’s largest phase 2b clinical trial—the Transplantation Without Overimmunosuppression (TWO) Study. With promising preliminary results at phase 1, understanding the dominant mechanisms by which Treg control the transplant alloresponse is of critical importance from both the perspective of biomarker discovery and to inform the development of next-generation therapies.

In this thesis, we perform a longitudinal multiomic study to systematically evaluate the impact of adoptive Treg transfer on the transcriptome, immune repertoire, and cell surface phenotype of immune cells within peripheral circulation and the transplanted kidney. We uncover compositional, functional, and phenotypic changes that follow Treg cell therapy and propose a role of local immune regulation within the transplant as a key mechanism of action. In the second part of this thesis, we evaluate two next-generation Treg cell therapy strategies designed to enhance the potency and generalisability of the therapeutic approach, demonstrating feasibility of third-party allogeneic Treg therapy facilitated by HLA-modulating genetic edits, and of a TCR fusion construct Treg to redirect endogenous TCR signalling towards a clinically relevant antigen. The findings and resources presented in this thesis offer deeply granular insights into the biology of human adoptive Treg transfer, uncovering translatable observations to inform the design and development of next- generation cell therapy products.

Authors: McCallion, O

• DOI: 10.5287/ora-5rekxj2oe
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English