Donor-derived and third-party antigen specific T cells for the prevention and treatment of disease relapse and infection post allogeneic haemopoietic stem cell transplantation

Abstract

Allogeneic haemopoietic stem cell transplantation (HSCT) remains the only curative option for a significant number of malignant and non-malignant haematological diseases. The prolonged period of impaired recipient immunity following transplantation drives disease relapse, opportunistic infections and graft versus host disease, which are the leading causes of death in the first year following HSCT.

Adoptive cellular therapy through the transfer from donor to recipient of ex vivo isolated antigen-specific T cells is a promising strategy to rapidly restore immunity during this vulnerable period. This thesis explores several strategies to expand the application and utility of cellular therapies in the restoration of post-transplant immunity. Chapter 3 is a clinical trial of patients with CMV and EBV infection treated upfront for first viral reactivation, in contrast to existing studies to date that have used this therapy in the setting of recurrent or refractory infections. Chapter 4 is a clinical trial reporting the safety, efficacy and feasibility of the novel use of tumour antigen-specific cell therapies in combination with multipathogen-specific cell therapies to prevent relapse and opportunistic infection following HSCT for high risk myeloid malignancies. Chapter 5 describes the development of novel T cell products for a cellular therapy bank targeting BK virus and human herpesvirus 6, two pathogens that cause significant morbidity and mortality post-HSCT, for use in an upcoming clinical trial.

The work reported in this thesis adds novel insights to the current knowledge base and provides avenues for further study through exploratory early phase and larger randomised trials that will facilitate the incorporation of adoptive cellular therapies into future routine clinical practice.