Graft versus host disease (GvHD) prevention in allogeneic hematopoietic stem cell transplantation: T cell depletion strategies to reduce GvHD risk while preserving graft versus tumor (GvT) effect

Abstract

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a well-establishedtherapeutic approach for a wide range of malignant and non malignant hematologicdiseases, often offering the only curative option. AlloHSCT success, based on the immunegraft-vs-tumor (GvT) effect, is hampered by graft-vs-host disease (GvHD), major cause ofmorbidity and nonrelapse mortality. Optimal GvHD prophylaxis would prevent clinicallysignificant GvHD while maintaining GvT effect and allowing immune reconstitution.Transplant modalities may be modified to reduce GvHD risk, but the basis of GvHDprophylaxis is still the pharmacological inhibition of T cell activation and proliferation by acalcineurin inhibitor associated to an anti-metabolite as described almost 40 years ago.Graft engineering to safely reduce GvHD risk while preserving GvT is a challenging area ofresearch. Most of the strategies consist in a kind of graft T cell depletion (TCD), whichhowever is associated with delayed immune reconstitution and increased risk of relapse.Different TCD approaches exist including ex vivo TCD (graft manipulation by negative orpositive selection before infusion), or in vivo TCD (administration of medications, such asanti-thymocyte globulin, cyclophosphamide or alemtuzumab to the patient before or/and aftergraft infusion). Geneva’s TCD approach is a partial TCD (pTCD) consisting in in vitro TCD by “alemtuzumabin the bag” of a part of the graft followed by an add-back of unmanipulated graft containing afixed dose of T cells. We consider that our approach of pTCD for GvHD prevention mitigatesthe disadvantages of extensive TCD methods and may abrogate severe GvHD, resulting inlow transplant related morbidity and mortality and better quality of life, without weakening thecurative potential of alloHSCT. We believe that it is particularly beneficial in case oftransplantation for severe aplastic anemia, and potentially other benign diseases, wherepTCD provides peripheral blood stem cell grafts containing a high number of hematopoieticstem cells and a sufficient number of T cells to ensure engraftment with low GvHD risk, andfor chronic myeloid leukemia where pTCD decreases GvHD risk in the early post-transplantperiod, while postponing a possible molecular relapse of the disease to a time when thepatients could achieved complete remission by donor infusion lymphocytes without importantrisk of GvHD. Efforts to modify T cell composition of the graft in favor of lymphocyte subsets reported to bemore important mediators of GvT than GvHD by more refined and sophisticated techniquesof TCD have been made. The results are promising, improving both efficacy and safety ofalloHSCT, but wide implementation of these methods is not possible yet.</p