Stem Cell Transplant With Th2/Tc2 Cells to Treat Advanced Breast Cancer
Condition: Breast Neoplasms
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      This Phase 1 trial will investigate the safety of a modified stem cell transplant procedure
      for treating advanced breast cancer. Patients with cancers can sometimes benefit greatly from
      transplants of stem cells (cells produced by the bone marrow that mature into blood cells).
      In addition to producing new bone marrow and restoring normal blood production and immunity,
      the donated cells fight any residual tumor cells that might have remained in the body, in
      what is called a "graft-versus-tumor" effect. However, severe problems, or sometimes even
      death, may follow these transplants as a result of the high-dose chemotherapy and radiation
      that accompany the procedure. Also, donated immune cells called lymphocytes, or T cells,
      sometimes attack healthy tissues in a reaction called graft-versus-host-disease (GVHD),
      damaging organs such as the liver, intestines and skin. This study will use the following
      strategies to try to reduce these risks:

        -  "Induction chemotherapy" to reduce patients' immunity in an attempt to prevent rejection
           of the donated stem cells

        -  Reduced-intensity conditioning chemotherapy that is easier for the body to tolerate and
           involves a shorter period of complete immune suppression

        -  Removal of lymphocytes from the donor stem cells for transfusion in small quantities at
           monthly intervals following the stem cell transplant to reduce the risk of GVHD

        -  Transplant of specific lymphocytes called Th2/Tc2 cells that may increase the percentage
           of donor stem cells accepted by the patient without significantly increasing GVHD

      Patients between 18 and 75 years of age with advanced (stage IV) breast cancer that does not
      respond to standard therapy may be eligible for this study. Candidates are screened with a
      medical history, physical and dental examinations, x-ray studies and bone marrow biopsies to
      evaluate disease status, blood and urine tests (including a blood test for genetic match with
      the donor), and lung and heart function tests.

      Participants have a central venous line (large plastic tube) placed into a major vein. This
      tube stays in the body during the entire treatment period for infusing the donated stem cells
      and T lymphocytes, giving medications, including chemotherapy and other drugs, antibiotics,
      and blood transfusions, and withdrawing blood samples. Treatment starts with induction
      chemotherapy, in which patients receive one or two cycles of the anti-cancer drugs
      fludarabine and cyclophosphamide. (One cycle consists of 4 days on drug therapy followed by a
      17-day rest period.) G-CSF, a drug that boosts white cell production, is also given to reduce
      the risk of infection. Several days before the transplant procedure, patients begin
      conditioning chemotherapy with higher doses of cyclophosphamide and fludarabine. Three days
      after the conditioning therapy is completed, the stem cells are infused. To help prevent both
      rejection of the donor stem cells and GVHD, patients receive cyclosporine (first by vein and
      later by mouth) for several weeks after the transplant. Infusions of donor lymphocytes begin
      about 6 weeks after the transplant to boost the immune system and enhance the
      graft-versus-tumor effect.

      Patients may leave the hospital when they are able to eat and drink, have no fever or
      infection, and have a normal or near-normal white cell count. They return for follow-up
      visits twice a week for the first 100 days after the transplant, then every 3 months, then 6
      months and then yearly for at least 5 years post-transplant. The visits include a medical
      history, physical examination, and blood draws, as well as disease staging with CT scans
      every month for the first 6 months.
    

Detailed description: 
      Background:

        -  In CC# 00-C-0119 we were able to demonstrate that allogeneic T cells could mediate a
           clinically relevant graft-versus-tumor (GVT) effect against MBC after a
           reduced-intensity, T cell depleted allogeneic hematopoietic stem cell transplant
           (alloHSCT).

        -  Responses were observed after establishment of complete lymphoid chimerism, which was
           frequently delayed and required the use of planned donor lymphocyte infusions (DLI). DLI
           were associated with a significant incidence of graft-versus-host disease (GVHD).

        -  In murine models, in vitro generated T cells of Th2/Tc2 phenotype can facilitate
           engraftment of HLA disparate allografts with significantly reduced GVHD as compared to T
           cell replete allografts that have not been manipulated. In addition, Th2/Tc2 cells
           provide an anti-tumor effect through the perforin/granzyme pathway.

        -  Allogeneic Th2/Tc2 cells may facilitate rapid allo-engraftment post-transplant with
           reduced GVHD. In addition, the perforin-mediated anti-tumor activity of Th2/Tc2 cells
           should provide earlier benefit compared with T-cell depleted allografts.

      Objectives:

      -To determine the safety, as defined by the incidence of acute graft-versus-host disease, and
      feasibility of administering in vitro generated donor T cells of Th2/Tc2 phenotype to augment
      a T cell depleted allograft (T cell exchange) after reduced-intensity conditioning.

      Eligibility:

        -  Patients with measurable, metastatic breast cancer and an HLA matched sibling donor

        -  Patients must have received treatment with a taxane, an anthracycline, a hormonal agent
           and/or Herceptin, if the tumor expresses the respective receptors, and at least one
           treatment for metastatic disease that has not resulted in a complete response.

      Design:

        -  Donors will initially have lymphocytes collected to generate the Th2/Tc2 product and
           then have blood stem cells collected following mobilization with filgrastim. The stem
           cell product will be T-cell depleted, and the T-cell dose will be adjusted to 1 x 10(5)
           CD3+ cells/kg.

        -  Patients will receive induction (immune depleting) chemotherapy with the goal of
           reducing circulating CD4+ cell less than 50/microliter prior to proceeding to alloHSCT.

        -  Patients will receive a reduced-intensity conditioning regimen consisting of fludarabine
           and cyclophosphamide. This will be followed by infusion of the T cell depleted
           allograft, which will be supplemented with Th2/Tc2 cells (i.e. T cell exchange).

        -  Cyclosporine will be discontinued after 40 days to permit a full GVT effect. Patients
           may receive donor lymphocyte infusions at days +42, +70, +98 post-transplant to further
           potentiate a GVT effect.

        -  Patients will be enrolled in three cohorts, with escalating Th2/Tc2 cell doses (0.5 -
           12.5 x 10(7) cells/kg) given in a phase-I manner.
    

Intervention name(s): Th2/Tc2 Cells
Intervention type(s): Drug
Primary purpose: Treatment
Keywords: Engraftment; Graft-Versus-Host Disease; Metastatic Breast Cancer; MBC