Allogeneic Breast Protocol 2: Phase I Trial of T Cell Exchange With Th2/Tc2 Cells for Allogeneic Stem Cell Transplantation After Reduced Intensity Conditioning for Metastatic Breast Cancer
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.
Interventional
Primary Purpose: Treatment
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 after reduced-intensity conditio...
Daniel H Fowler, M.D.
Principal Investigator
National Cancer Institute (NCI)
United States: Federal Government
040131
NCT00079625
March 2004
March 2009
Name | Location |
---|---|
National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |