T Cell Therapy in Allogeneic Stem Cell Transplantation (2007)

T cells derived from healthy stem cell donors can mediate curative immune responses after allogeneic stem cell transplantation (SCT) by eliminating (residual) hematopoietic tumor cells life-threatening viral infections. The first evidence for the crucial role of T cells came from the observations that depletion of T cells from a stem cell graft to prevent the development of acute graft versus host disease (GVHD) was associated with an increased incidence of relapse of the malignancy and life threatening viral infections including CMV disease and EBV mediated post-transplant lymphoproliferative disease (PTLD). Apparently, after allogeneic SCT T cells are not only responsible for the detrimental GVHD, but also can mediate a graft versus tumor (GVT) effect and are essential for long term of control of persistent endogenous viral infections. Unmanipulated T cell populations derived from the stem cell donor administered to the patient may result in concurrent development of GVHD, GVT and anti-virus responses. Immune suppression to control GVHD may lead to reduction or elimination of GVT and pathogen specific T cell responses. Obviously, if T cell responses leading to GVHD could be separated from GVL or pathogen-specific reactivity, morbidity and survival after allogeneic SCT can be significantly improved. One approach to manipulate the effect of donor T cells after transplantation has been the depletion of donor T cells from the graft with postponed administration of donor T cells 1. The rationale for this approach came from several mouse and human studies illustrating that the recipient microenvironment plays a significant role in the development of GVHD2. Tissue damage during the conditioning regimen leading to the initiation of a ‘cytokine storm’, the strong lymphodepletion after transplant leading to homeostatic proliferation of donor T cells shortly after transplant, and the presence of patient derived activated dendritic cells (DC) which are required for the induction of allo-immune responses all contribute to these strong allo-response immediately after transplantation. Postponed T cell administration at the time of replacement of the majority of recipient DC by donor DCs, after repair of the tissue damage, and after partial reconstitution of T cells in peripheral blood of patients is associated with lower risk of developing severe acute GVHD. Administration of T cells from 6 months after transplantation can be performed with relatively low risk of inducing severe GVHD, although chronic GVHD remains a significant complication. However, recurrence of the malignancy and the development of severe opportunistic infections frequently take place within the first half year after transplantation. Thus, although postponed administration of T cells can result in less severe GVHD, overall survival did not significantly improve.

Delivering stem cell transplants that are free from GVHD while conferring enhanced protection against malignant disease recurrence and viral reactivation is considered by many transplanters to be a key goal (the “Holy Grail”) for improving transplant success. We will discuss several approaches for the selective administration of non-GVHD reactive donor T cells: selective allodepletion, adoptive transfer of virus-specific T cells, allo-reactive anti-tumor T cells recognizing minor histocompatibility antigens (mHag) or MHC molecules, or T cells recognizing tumor-associated self antigens.