Multiple Myeloma Clinical Trial
Official title:
Pilot Study of Donor Th2 Cells for the Prevention of Graft-Versus-Host Disease in the Setting of Non-Myeloablative, HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation
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.
Allogeneic peripheral blood stem cell transplantation (PBSCT) is primarily limited by
graft-versus-host disease (GVHD). In murine models, we found that donor CD4+ Th1 cells
(secretion of IL-2 and IFN-Gamma) mediate GVHD. In contrast, donor Th2 cells (secretion of
IL-4 and IL-10) do not generate GVHD, and abrogate Th1-mediated GVHD. We also found that
murine allografts enriched with Th2 cells reduced GVHD without impairing the ability of donor
T cells to prevent graft rejection. These studies indicate that donor Th2 cells may be a new
approach to reducing GVHD.
In addition to GVHD, allogeneic PBSCT has been limited by toxicity associated with
conventional myeloablative preparative regimens. Although non-myeloablative regimens may
reduce regimen-related toxicity, such transplants have been associated with a 30 to 40%
incidence of severe acute GVHD (similar to rates observed with myeloablative regimens).
Because non-myeloablative regimens appear to have reduced regimen-related toxicity, we have
conducted this pilot study of Th2 cells in the setting of an immunoablative
(non-myeloablative) preparative regimen.
In this protocol, patients with lymphoid or hematologic malignancy receive induction therapy
(fludarabine and EPOCH) and transplant chemotherapy (fludarabine and cytoxan) to deplete host
T cells that mediate graft rejection. In our initial NCI cohort receiving HLA-matched
sibling, G-CSF mobilized PBSCT on this protocol (n=19), graft rejection was prevented in all
cases, with most recipients having 100% donor chimerism by day 28 post-SCT. With this reduced
intensity regimen, GVHD remained a significant complication, with 6/19 recipients having
grade II and 6/19 recipients having grade III acute GVHD. Importantly, potent
graft-versus-tumor responses were observed, with 9/19 patients remaining in complete
remission at a median of 17 months post-SCT.
Given that this allogeneic SCT regimen achieves engraftment and durable anti-tumor responses,
yet is associated with GVHD, this protocol represents an appropriate setting for evaluation
of donor Th2 cells. Initial patients will receive Th2 cells in a phase I manner. Three
patients will receive 5 x 10(6) Th2/kg, six patients will receive 2.5 x 10(7) Th2/kg, and six
patients will receive 1.25 x 10(8) Th2/kg. The highest dose of Th2 cells that results in an
acceptable toxicity profile (not more than 1/6 serious adverse events) and a favorable rate
of acute GVHD (not more than 2/6 cases of grade II or greater acute GVHD) will be selected
for the phase II study arm. Eighteen patients will be treated with allogeneic SCT and Th2
cells on this phase II study arm. In the event that Th2 recipients have reduced GVHD, further
clinical trials involving Th2 cells will be warranted.
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