Developing translatable TetraVecta-enabled allogeneic regulatory T cell therapy

Co-supervisor: Prof. Joanna Hester, Nuffield Department of Surgical Sciences

Commercial partner: Oxford Biomedica (UK) Ltd (OXB)

Pathological immune activation is a hallmark of several diseases from autoimmunity to solid organ transplant rejection. At present the mainstay of treatment for patients remains non-specific immunosuppression with multiple side effects. Adoptive regulatory T cell therapy (Treg ACT) is a novel therapeutic strategy pioneered by our lab in which Treg are isolated and expanded under good manufacturing compliant conditions. At phase 1 we demonstrated that Treg ACT is both safe and feasible in addition to observing encouraging preliminary efficacy signals. We are currently undertaking the world’s largest phase 2 randomised controlled trial of Treg ACT for recipients of living donor kidney transplants.

Consideration of how Treg ACT may be scaled-up to have broad therapeutic applicability is now warranted, given the economic, logistic, and technical barriers inherent in a bespoke autologous therapy. Several such barriers could be overcome by an allogeneic strategy utilising cells from a universal donor. However, unmodified allogeneic cells would be recognised and promptly rejected by the intact recipient immune system, predominantly driven by recognition of foreign human leukocyte antigen class 1 and class 2 molecules. We have successfully knocked out HLA class 1 and class 2 from primary human Treg and have demonstrated equivalent function to autologous Treg in a humanised skin transplant rejection model (McCallion, Hester, & Issa et al. under submission).

Building on our preliminary data, this project broadly aims to develop and evaluate novel lentiviral editing strategies to modulate HLA expression both in isolation or alongside additional functional or phenotypic edits, under the MRC industrial strategy priority topics of advanced therapies, precision medicine, and translational development.

The specific aims of the project are:

1. To compare transduction efficacy of HLA-modulating edits in primary human Treg between platforms (TetraVecta, classical lentiviral transduction, electroporation).
2. To functionally and phenotypically screen candidate HLA-modulation strategies including transcriptomic and proteomic analysis using in-house single cell RNA sequencing facilities.
3. To evaluate ‘off-the-shelf’ Treg cell therapy candidates in well-established humanised models of transplant rejection.

Objectives 1 and 2 will be progressed concurrently during the first 24 months of the studentship, which will also include the 3-month industry placement at OXB. Objective 3 will be performed between months 24 and 36. During the final 12 months, 8 months will be dedicated to completion experiments and 4 months will be ringfenced for write-up and viva. The project is therefore feasible within the iCASE studentship timescale.

The successful applicant will have the exciting and unique opportunity to work with Oxford Biomedica (OXB) and the Translational Research and Immunology Group (TRIG) at the University of Oxford. OXB is a leading cell therapy and synthetic biology company owning the proprietary TetraVecta fourth-generation lentiviral transduction platform who, in partnership with Novartis, brought one of the first autologous cell therapy products to market (Kymriah). TRIG has over 20 years of experience in preclinical and clinical evaluation of regulatory cell therapies. This iCASE studentship represents an exciting and mutually beneficial opportunity for OXB and TRIG to combine expertise and develop candidate allogeneic regulatory T cell therapeutic strategies.

Apply using course: DPhil in Surgical Sciences