Donor Th2 Cells to Prevent Graft-Versus-Host Disease in Bone Marrow Transplants
Condition: Chronic Lymphocytic Leukemia; Graft vs Host Disease; Hodgkin's Disease; Multiple Myeloma; Non Hodgkin's Lymphoma
MeSH terms: Leukemia; Multiple Myeloma; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Hodgkin Disease; Graft vs Host Disease
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      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.
    

Intervention name(s): Th2 cells in allo HSCTT; Th2 Cells
Intervention type(s): Drug; Drug
Primary purpose: Treatment
Keywords: Bone Marrow Transplantation; Chronic Lymphocytic Leukemia; Immunotherapy; Lymphoma; Multiple Myeloma; Graft vs. Host Disease; Lymphoid Malignancy; Leukemia