Can graft-versus-leukemia reactivity be dissociated from graft-versus-host disease?

Abstract

Dissociation of graft-versus-leukemia (GvL). effects from graft-versus-host disease (GvHD) is the ultimate goal of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of hematological malignancies. The pivotal role of donor T cells in both anti-leukemic and anti-host reactivity of allogeneic stem cell grafts has been known since the first transplants for fatal leukemia were performed over 25 years ago. Growing understanding of the T cell-mediated GvL response has revealed the importance of host-type antigen-presenting cells and the capacity of adoptively transferred donor T cells in inducing anti-leukemic responses, and has led to a re-evaluation of the relative roles of the pre-transplant conditioning regimen and the allogeneic stem cell graft. Key advances in clinical practice such as reduced-intensity stem cell transplantation and donor lymphocyte infusions are now routinely applied and allow for the induction of potent antileukemic effects, while GvHD can to some extent be controlled. Other strategies to separate T cell-mediated antileukemic effects from GvHD are antigen-specific adoptive T cell-therapy and recipient lymphocyte infusion (RLI) and these are in an experimental stage. Importantly, a role for alloreactive natural killer cells in mediating GvL without GvHD has emerged in patient studies of MHC haplotype-mismatched alloHSCT. Finally, experimental studies indicate that naturally occurring regulatory T cells may differentially affect GvHD and GvL.

Alteration of enzyme specificity by computational loop remodeling and design

“…We applied the method to altering the specificity of human guanine deaminase (hGDA) with the long-term goal of introducing cytosine deaminase activity into a human protein scaffold. A designed cytosine deaminase with a sequence close to that of a human protein would solve an important problem in suicide gene therapy (16)(17)(18) by providing prodrug-activating ability (19)(20)(21)(22) while retaining low immunogenicity, as described in the SI Text. We consider hGDA to be the best starting point for such an effort based on the complement of deaminases that exist in the human genome (23,24).…”

CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation

“…23 Available data suggest that the presence of both recipient-derived antigen-presenting cells and possibly cytokine release associated with regimen-related toxicity may be components that participate in the generation of clinical acute GVHD. 23 The lack of one or both of these components due to the relatively prolonged time between last donor-cell infusion and ipilimumab administration may have contributed to the lack of clinical acute GVHD seen after ipilimumab despite the other immune effects observed. Delayed administration of anti-CTLA4 antibody was associated with augmentation of the GVM effect without exacerbation of lethal GVHD in a murine model of MHC-mismatched allo-HCT.…”

Role of Interleukin-15 in Umbilical Cord Blood Transplantation

“…The mechanism that enhances the antitumor effect may also aggravate GVHD in the context of allogeneic transplantation [86,87]. In allogeneic UCB transplantation, however, reduced GVHD severity is not associated with an increased relapse rate relative to other donor sources [9,19], suggesting that the GVL effect of the UCB graft is well maintained.…”