Next Generation T-cell therapies for CMV post-allogeneic stem cell transplant

Funding is requested to support a Phase I, single-centre, open-label clinical trial of Glucocorticoid Receptor (GR) knockout CMV-specific T-cells (CMV-ko) for an unmet clinical need i.e. HLA-A0201 patients with drug-resistant CMV infection requiring concurrent glucocorticoid therapy for GvHD. This study represents a first-in-man application of genome-edited CMV-specific T-cells to patients.

We will manufacture 8-10 patient products over 2-years and endpoints will include manufacturing feasibility and read-outs for toxicity and efficacy.

If Phase I data is compelling, we will apply for follow-on funding for a Phase I/II extension and will broaden inclusion criteria to patients/donors beyond HLA-A0201.

CMV-ko may become an alternative/adjunct to antiviral pharmacotherapy and if this were the case, we would propose a pathway to clinic with a commercial partner, or potentially via an academic funder.

Longer-term we hope to generate a genome-editing platform to ‘knock-out’ a range of critical receptors targeted by frequently-used immunosuppressants (CD52/Campath; Cyclophillins/Ciclosporin; FK-binding proteins/Tacrolimus).

We aim to apply this platform to engineered T-cell immunotherapies to permit engraftment, expansion and persistence in patients where immunosuppressants cannot be readily stopped.

This would be valuable for antiviral indications (CMV/EBV/Adenovirus) but also for cancer indications such as Chimeric-Antigen-Receptor (CAR) T-cells, Tumour-Infiltrating-Lymphocytes (TILs) and for TCR-T-cell therapies.