Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation

Abstract

Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potentially curative therapy for many hematologic and immunologic diseases. Further, partial or full donor hematopoietic chimerism following alloSCT may be sufficient to guarantee immunologic tolerance to solid organs from the same donor, obviating any requirement for prolonged pharmacologic immunosuppression. Despite alloSCT's potential, the procedure is beset by two major limitations. The first relates to the procedure's toxicity, including conditioning regimen toxicity, graft-versus-host disease (GVHD), and infection. The second limitation is the lack of histocompatible donors. A human leukocyte antigen (HLA)-matched sibling or unrelated donor cannot be identified expeditiously for up to 40% of patients. Historically, alloSCT from partially HLA-mismatched, or HLA-haploidentical, relatives has been complicated by unacceptably high incidences of graft rejection, severe GVHD, and non-relapse mortality. Recently, our groups have developed a method to selectively deplete alloreactive cells in vivo by administering high doses of cyclophosphamide in a narrow window after transplantation. Using high-dose, post-transplantation cyclophosphamide (PT/Cy), crossing the HLA barrier in alloSCT is now feasible and donors can be found for nearly all patients. This review discusses the history of HLA-haploidentical SCT, recent clinical results, and immunologic mechanisms of action of high-dose PT/Cy for prevention of graft rejection and GVHD.

Figure 1. Proposed mechanism and stages for the induction of transplantation tolerance by high-dose cyclophosphamide

A) Mechanisms of tolerance induction with PT/Cy. The promotion of tolerance through induction of donor hematopoietic chimerism with PT/Cy can be viewed as a three-step process. The first step occurs after alloreactive T cells undergo proliferation. The replicative DNA synthesis renders alloreactive proliferating T cells uniquely sensitive to Cy. Both anti-host and anti-donor T cells are selectively destroyed with PT/Cy administered on day +3. The persisting donor T cells contribute to a peripheral T cell pool whose composition of effector and regulatory T cells determines the post-transplant clinical outcomes. After transplantation, the graft goes through a transition during which the alloreactive and regulatory forces come into balance. The third step is characterized by intrathymic clonal deletion of donor-HSC-derived, anti-host T cells in the thymus. The de novo thymically-derived T cells also contribute to the peripheral T cell pool and influence the clinical outcomes, although their contribution may be delayed for months to years after allografting depending on the species and age of the host. B) Sequential stages of tolerance induced by PT/Cy. The “induction phase” refers to the period characterized by the PT/Cy-induced clonal destruction of alloreactive T cells. Given that the degree of clonal destruction with Cy is dependent on the size of the alloreactive T cell burden, and likely incomplete especially in an HLA-mismatched setting, there is a transition phase and a need for constraining the persistent non-deleted alloagressive T cell clones. We hypothesize that the metastable phase during which the alloreactive and regulatory forces come into balance and central tolerance becomes operational precedes development of the full tolerance. In the clinic, this is a period dominated by relevant clinical outcomes such as delayed rejection or GVHD, and these responses are controlled with the use of other immunosuppressive drugs after PT/Cy. How these drugs influence immunoregulatory mechanisms and whether rejection or GVHD represent the failure to establish the balance between alloagressive effector T cells and Tregs needs to be determined. The ultimate development of tolerance and the establishment of mechanisms that maintain this process results in the withdrawal of all immunosuppressants. HSC (hematopoietic stem cells). Teff (Effector T cells). Treg (Regulatory T cells).