Understanding the mechanisms that promote functional immunological control of human cytomegalovirus in solid organ transplant patients

CD8+ cytotoxic T lymphocytes are critical for the efficient immune surveillance of persistent infection with human cytomegalovirus (CMV). In the immune-suppressed environment that occurs to suppress graft rejection following solid-organ transplantation (SOT), inhibition of viral reactivation is dependent upon the administration of ganciclovir. intolerance in the absence of stable immunity can result in persistent viral infection resulting in end-organ disease. Adoptive cellular therapy (ACT) with CMV-specific T cells offers an alternate approach to promote immune reconstitution in SOT recipients. We have recently completed a first in man phase I clinical trial of autologous ACT to treat CMV complications in SOT patients, demonstrating the safety of this approach. The project will focus upon understanding the mechanisms that promote efficient functional reconstitution in SOT patients following ACT. Our preliminary observations suggest that improved immune reconstitution is linked to earlier intervention with ACT, prior to the establishment of dysfunctional immunity.

Aims:
1. To examine the factors that affect immunological reconstitution following CMV specific T cell adoptive cell therapy post-transplant.
2. To determine if differences in pre-existing viral immunity predispose lung transplant recipients to post-transplant CMV-associated complications.
3. To modulate at the epigenetic level the putatively identified molecular markers in order to enhance the functional capacity of virus-specific T cells for ACT.
4. To develop antigen-specific T cells as a platform to express chimeric antigenic receptors (CAR) against novel targets in malignancies.

For more information on this research group: http://www.qimrberghofer.edu.au/lab/translational-human-immunology/