Donor Th2 Cells to Prevent Graft-Versus-Host Disease in Bone Marrow Transplants

NCT00001830 | Completed Phase 1

• 2 other identifiers: 99014399-C-0143
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Lymphocytic Leukemia; Graft vs Host Disease; Hodgkin's Disease; Multiple Myeloma; Non Hodgkin's Lymphoma

Keywords

Bone Marrow Transplantation; Chronic Lymphocytic Leukemia; Immunotherapy; Lymphoma; Multiple Myeloma; Graft vs. Host Disease; Lymphoid Malignancy; Leukemia

Interventions

Th2 cells in allo HSCTT DRUG

Th2 Cells DRUG

Eligibility Criteria

• Age: 12 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with lymphoid malignancy and leukemia (including myelodysplasia) are candidates for this study. The following diagnoses and ages will be considered:
• Chronic Lymphocytic Leukemia, Age 18-75
• Relapse Post-fludarabine, or
• Non-CR after Salvage Regimen
• Hodgkin's and Non-Hodgkin's Lymphoma (all types, including Mantle Cell Lymphoma), Age 18-75
• Primary Treatment Failure, or
• Relapse after AutoSCT, or
• Non-CR after Salvage Regimen
• Multiple Myeloma, Age 18-75
• Primary Treatment Failure, or
• Relapse after AutoSCT, or
• Non-CR after Salvage Regimen
• Acute Myelogenous Leukemia, Age 18-75
• In CR #1, 2, or 3
• Any Relapse with less than 10% blasts (marrow and blood)

You may not qualify if:

• Infection that is not responding to anti-microbial therapy.
• Active CNS involvement by tumor.
• HIV positive (due to unacceptable risk after allogeneic transplantation).
• Hepatitis B or C surface antigen positive.
• Lactating or pregnant females (due to risk to fetus or newborn).
• History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent (as determined by principal investigator or study chairman).
• History of psychiatric disorder which may compromise compliance with transplant protocol, or which does not allow for appropriate informed consent.
• History of hypertension that is not controlled by medication, stroke, or severe heart disease. Individuals with symptomatic angina, or a history of coronary artery bypass grafting or angioplasty will be considered to have severe heart disease, and thus will not be eligible to be a donor.
• Anemia (Hb less than 11 gm/dl) or thrombocytopenia (PLT less than 100,000 per ul).
• Lactating or pregnant females.
• HIV positive.
• Hepatitis B or C antigen positive.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Wasch R, Bertz H, Kunzmann R, Finke J. Incidence of mixed chimaerism and clinical outcome in 101 patients after myeloablative conditioning regimens and allogeneic stem cell transplantation. Br J Haematol. 2000 Jun;109(4):743-50. doi: 10.1046/j.1365-2141.2000.02110.x.

  PMID: 10929024 BACKGROUND

• Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, Read EJ, Carter C, Bahceci E, Young NS, Barrett AJ. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood. 1999 Nov 1;94(9):3234-41.

  PMID: 10556212 BACKGROUND

• Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L, Romanelli A, Vinci M, Pinotti G, Lambelet P, Loni C, Verdiani S, De Stefano F, Valbonesi M, Corsetti MT. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol. 2000 Dec 1;18(23):3918-24. doi: 10.1200/JCO.2000.18.23.3918.

  PMID: 11099321 BACKGROUND

• Jamshed S, Fowler DH, Neelapu SS, Dean RM, Steinberg SM, Odom J, Bryant K, Hakim F, Bishop MR. EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011 May;46(5):676-81. doi: 10.1038/bmt.2010.173. Epub 2010 Jul 26.

  PMID: 20661232 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Graft vs Host Disease; Hodgkin Disease; Multiple Myeloma; Lymphoma, Non-Hodgkin; Lymphoma; Leukemia

Interventions

prostaglandin D2 receptor

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders

Study Officials

• Daniel H Fowler, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Purpose: TREATMENT
• Sponsor Type: NIH

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: November 4, 1999
• Study Start: July 20, 1999
• Study Completion: May 19, 2015
• Last Updated: July 5, 2018

Record last verified: 2015-05-19

Locations

US (1)