Naive T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation

Trial Information

Naive T-Cell Depleted Donor Lymphocyte Infusion Following Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (SCT) offers the hope of cure for a wide variety of
hematologic malignancies. Mature donor T-cells play a critical role in the success or
failure of this procedure. A subset of donor T-cells mediates graft-versus-host disease
(GvHD). Other subsets provide the foundation for immune recovery. Pan-depletion of mature
donor T-cells is an obligate step in haploidentical allogeneic stem cell transplantation.
Without this step, the recipient would succumb to lethal acute GVHD. We have had extensive
experience with in-vivo donor (and recipient) T-cell depletion using alemtuzumab as part of
the bone marrow conditioning regimen. We and others have also used anti-thymocyte globulin
for the same purpose. Pan-depletion of T-cells eliminates GvHD but significantly increases
the risks of tumor relapse and opportunistic infections. A delayed donor lymphocyte
infusion augments immune recovery and the graft versus tumor response, but it comes at the
risk of inducing lethal GvHD. This is particularly problematic when the donor and recipient
are HLA-discordant. Thus the major challenge in allogeneic stem cell transplantation is
determining how to maximally exploit the beneficial effects mediated by T-cells without
causing GvHD. This challenge could be overcome by selectively depleting the population of
donor T-cells responsible for eliciting the GvHD response. We have been interested in
selecting T-cells based on their naïve or memory phenotype to understand the contribution of
each of these cells to the pathogenesis of GvHD. Naïve T-cells (CD62L+ or CD45RA+) are
T-cells that have not encountered antigens specific for their T-cell receptor. Memory
T-cells (CD62L- or CD62L+ or CD45RA-) are T-cells that have previously been exposed to their
corresponding cognate antigens. If a donor has not encountered host alloantigens,
GvHD-inducing host-reactive T-cells should be contained in the naïve T-cell compartment. In
contrast, all the memory phenotype cells should not recognize host alloantigens. If this
hypothesis is correct as suggested by several published studies, CD62L- T-cells, which are
devoid of naïve T-cells and represent a subset of memory T-cells, should not be able to
induce GvHD. The study hypothesis is depletion of naïve T-cells from the donor lymphocyte
inoculum will abrogate GVHD while providing immunocompetent memory T-cells to affect an
anti-infection and a graft versus tumor response. In this study, we will determine the
maximum tolerated dose of a naïve T-cell depleted donor lymphocyte infusion given to
patients following HLA-matched and HLA-mismatched, allogeneic stem cell transplantation. We
will assess the GVHD-inducing potential of this donor lymphocyte infusion and further
monitor the impact that this DLI will have on post-transplant immune recovery.