Third-party virus-specific T-cells can provide long-term viral control without toxicity in allogeneic haemopoietic stem cell transplant patients with recurrent or refractory viral infection

Abstract

Viral infections are a significant source of morbidity and mortality following allogeneic haemopoietic stem cell transplantation (HSCT). HSCT constitutes the only curative therapy for many haematological malignancies. Global transplant practices are evolving with drive to meet demand leading to increased use of ‘alternative’ and ‘mismatched’ donors. These factors contribute to the delayed T-cell recovery with increased vulnerability to latent viral reactivation. Use of antiviral therapy can be limited by resistance or toxicity. HSCT donor-derived virus-specific T-cells (VST) are an alternative for the prophylaxis or treatment of infection. Despite promising early phase trial results this form of therapy is unlikely to be adopted as a standard of care. A HSCT donor-derived product will not be available to all patients, and may not be available in situations of clinical urgency. On a broader scale, VST manufacture is not economical, as products are intended for a specific recipient and there is risk that products will not be used. The use of third-party donor VST is an alternative option. Feasibility has been demonstrated in a small number of studies using partially human leucocyte antigen (HLA)-matched third-party donor VST to treat viral infection in HSCT recipients. This thesis investigated optimal procedures for establishing a third-party bank of cryopreserved CMV, EBV, and Adv-specific T-cells within an existing HSCT program. Banked VST products were fully characterized for HLA type and antiviral activity. The long-term efficacy and safety of these VST products for treatment of refractory viral infection post-HSCT were investigated in a phase I multi-centre trial. The immunological impacts of third-party VST infusion were examined by measuring immune cell frequencies, cytokine activity, virus-specific T-cell frequency, and persistence of infused-third party cells in the post-treatment period. It is envisaged that the results of these investigations will contribute to the evaluation of third-party donor cell banks as a safe and pragmatic therapeutic approach worthy of later phase studies, in turn improving accessibility to highly efficacious and low toxicity antiviral treatment for all HSCT patients.