Adenovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are the three commonest causes of lethal viral disease in patients immunocompromised by allogeneic stem cell transplantation (SCT). No drugs are available to treat adenovirus or EBV infections, and conventional agents for CMV have many limitations. Hence there is considerable interest in the use of T-cell based therapies to restore immunity to these pathogens. The current application builds on this group's earlier work, showing that EBV specific CTL generated by culture of donor T cells with donor EBV-transformed lymphoblastoid cell lines (LCL) can be safely administered to SCT recipients and act as effective EBV prophylaxis. Moreover, gene marking the CTL before infusion showed that these cells persisted long term and infiltrated and destroyed sites of active EBV lymphoma. This grant now proposes to use the excellent antigen presenting properties of EBV-LCL to present additional antigens, derived from adenovirus and CMV, ultimately generating a CTL line from a single culture that has specificity for all three viruses. The three Specific Aims are based on substantial pre-clinical feasibility data.
In Aim 1, patients will continue to receive EBV-specific CTL but will receive in addition gene marked adenovirus specific CTL in a dose escalation study, to establish their safety and persistence.
In Aim 2, EBV-LCL themselves will be pulsed with adenovirus and used to generate bi-specific lines recognizing both EBV and CMV. These will be infused into patients and their persistence and anti-viral immune activity measured.
In Aim 3, EBV-LCL will be pulsed with both adenovirus and CMV, and tri-specific CTL lines prepared. Following infusion, their safety, persistence and anti-viral immune activity will be determined. This plan to develop a cell based anti-viral therapeutic that derives from a single culture system, will offer a practical and cost-effective means of preventing these three lethal infections after SCT.
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