Donor Th2 Cells to Prevent Graft-Versus-Host Disease in Bone Marrow Transplants
Status:
Completed
Trial end date:
2015-05-19
Target enrollment:
Participant gender:
Summary
Allogeneic peripheral blood stem cell transplantation (PBSCT) is primarily limited by
graft-versus-host disease (GVHD). In murine models, we have demonstrated that donor CD4+ T
cells of Th1 cytokine phenotype (defined by their secretion of IL-2 and IFN-gamma) mediate
GVHD. In contrast, donor CD4+ T cells of Th2 phenotype (defined by their secretion of IL-4,
IL-5, and IL-10) do not generate GVHD, and abrogate Th-1-mediated GVHD. Importantly, we have
demonstrated that enrichment of murine allografts with Th2 cells reduces GVHD without
impairing the ability of donor T cells to prevent graft rejection. These studies indicate
that the administration of Th2 cells after allogeneic transplantation represents a strategy
for achieving alloengraftment with reduced GVHD.
In addition to GVHD, allogeneic PBSCT has been limited by the toxicity associated with
conventional myeloablative preparative regimens. Such regimens, which typically utilize total
body irradiation (TBI) and high-dose chemotherapy, were once considered essential for the
prevention of graft rejection. However, recent clinical studies have shown that
non-myeloablative doses of fludarabine-based chemotherapy can result in alloengraftment. In
murine models, we have demonstrated that severe host T cell depletion induced by combination
fludarabine and cytoxan can prevent even fully-MHC mismatched marrow graft rejection.
Although non-myeloablative regimens may reduce regimen-related toxicity, such transplants
have been associated with a 30 to 40% incidence of severe acute GVHD that is similar to rates
observed with myeloablative regimens. Because non-myeloablative regimens appear to be
associated with reduced regimen-related toxicity, we have elected to conduct this phase I
study of Th2 cells in the setting of an immunoablative (non-myeloablative) preparative
regimen.
Patients with leukemia in clinical remission, and patients with refractory lymphoid
malignancy will be candidates for this HLA-matched allogeneic PBSCT protocol. Patients will
receive novel induction regimen (fludarabine and EPOCH) and transplant preparative regimen
(fludarabine and cytoxan) designed to maximally deplete host immune T cells capable of
mediating graft rejection. After induction and preparative regimen chemotherapy, patients
will receive an unmanipulated, G-CSF mobilized PBSC graft. In the initial six patients
receiving this transplant procedure at the NCI, graft rejection has been successfully
prevented (100% donor chimerism by day 30 post-transplant). Importantly, GVHD has been
observed in all six patients, with three of the six patients developing severe GVHD (grade
III). Given that this regimen successfully achieves donor engraftment, and is associated with
significant GVHD, this transplant regimen represents an excellent clinical setting for the
evaluation of Th2 cells.
Using this non-myeloablative allogeneic PBSCT approach, we will perform a Phase I study to
evaluate the safety and feasibility of administering donor Th2 cells on day 1
post-transplant. Prior to transplantation, donor CD4+ T cells will be stimulated in vitro
using culture conditions that support the generation of donor CD4 cells of the Th2 cytokine
profile. If this Phase I study demonstrates that Th2 cell administration is safe and
feasible, a Phase III study will be performed to evaluate whether Th2 cell administration
reduces the incidence and severity of GVHD. Successful implementation of this Th2 strategy
will greatly reduce the morbidity and mortality associated with allogeneic PBSCT, and may
also represent an approach to stem cell transplantation in patients lacking an HLA-matched
donor.