CMV-specific immune reconstitution following allogeneic stem cell transplantation

Abstract

Cytomegalovirus (CMV) remains a major contributor to morbidity and mortality following allogeneic haemopoietic stem cell transplant (HSCT) despite widespread use of viraemia monitoring and pre-emptive antiviral therapy. Uncontrolled viral replication occurs primarily in the first 100 d post transplant but this high risk period can extend to many months if immune recovery is delayed. The re-establishment of a functional population of cellular effectors is essential for control of virus replication and depends on recipient and donor serostatus, the stem cell source, degree of HLA matching and post-transplant factors such as CMV antigen exposure, presence of GVHD and ongoing use of immune suppression. A number of immune monitoring assays exist but have not yet become widely accessible for routine clinical use. Vaccination, adoptive transfer of CMV specific T cells and a number of graft engineering processes are being evaluated to enhance of CMV specific immune recovery post HSCT.

Keywords: CMV immunity; Cytomegalovirus; adoptive T cell transfer; haemopoietic stem cell transplantation; immunotherapy.

Figure 1.

CMV immune recovery post-allogeneic HSCT. (A and B) Absence of CMV reactivation does not stimulate clonal expansion of CMV specific T cell clones and detectable CMV immunity is low or undetectable. When CMV-VSTs are administered prophylactically no expansion of the transferred clones is observed. (C and D) Low level CMV reactivation is controlled by CMV-VSTs that recover in the first few months post-HSCT. Prophylactic or pre-emptively administered CMV-VSTs are seen to expand in vivo and produce long-lasting stable immunity that is detectable up to 10 y after transplant. (E) CMV immunity recovers and controls CMV without treatment in the first few months. Subsequent development of GVHD and administration of corticosteroids and other immune suppressive medications results in loss of CMV immunity and recurrent CMV reactivation requires treatment with antiviral pharmacotherapy. (F) After failure to establish an effective cellular immune response spontaneously, either due to treatment (as in E) or donor seronegativity, donor-derived or third party banked CMV-VSTs administered therapeutically can rescue patients refractory to standard therapies.