Ignite Creation Date:
2024-05-05 @ 10:00 AM
Last Modification Date:
2024-10-26 @ 9:02 AM
Study NCT ID:
NCT00001830
Status:
COMPLETED
Last Update Posted:
2018-07-05
First Post:
1999-11-03
Brief Title:
Donor Th2 Cells to Prevent Graft-Versus-Host Disease in Bone Marrow Transplants
Sponsor:
National Cancer Institute NCI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
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
Status:
COMPLETED
Status Verified Date:
2015-05-19
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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 n19 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 619 recipients having grade II and 619 recipients having grade III acute GVHD Importantly potent graft-versus-tumor responses were observed with 919 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 106 Th2kg six patients will receive 25 x 107 Th2kg and six patients will receive 125 x 108 Th2kg The highest dose of Th2 cells that results in an acceptable toxicity profile not more than 16 serious adverse events and a favorable rate of acute GVHD not more than 26 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
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 n19 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 619 recipients having grade II and 619 recipients having grade III acute GVHD Importantly potent graft-versus-tumor responses were observed with 919 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 106 Th2kg six patients will receive 25 x 107 Th2kg and six patients will receive 125 x 108 Th2kg The highest dose of Th2 cells that results in an acceptable toxicity profile not more than 16 serious adverse events and a favorable rate of acute GVHD not more than 26 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 99-C-0143 | None | None | None |