Trial of Adoptive Immunotherapy With TRACT to Prevent Rejection in Living Donor Kidney Transplant Recipients
Condition: End Stage Renal Disease
MeSH terms: Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 1

Summary: 
      Regulatory CD4+CD25+ T cells (Treg) derived from the thymus and/or peripheral tissues have
      been demonstrated to broadly control T cell reactivity (14). Importantly, Tregs have been
      shown to control immune responsiveness to alloantigens and significantly contribute to
      operational tolerance in transplantation models (15, 16). However, there have been limited
      efforts to harness the therapeutic potential of directly isolated CD4+CD25+ Treg cells for
      controlling graft rejection and inducing transplantation tolerance, such as for kidney
      transplants. In order for CD4+CD25+ Treg cells to be used as a clinical treatment, the
      following cell properties could be necessary: ex vivo generation of sufficient numbers of
      cells, migration in vivo to sites of antigenic reactivity, ability to suppress rejection in
      an alloantigen-specific manner, and survival/expansion after infusion for a critical, but
      currently unknown, period of time. Our published work and that of other investigators has
      demonstrated 1) the feasibility of expanding Treg ex vivo, 2) the ability of these cells to
      downregulate allogeneic immune responses in vitro, and 3) the efficacy of Treg for prevention
      of allograft rejection in animal models (15,16). We have developed strategies for the ex vivo
      expansion of naturally occurring human Tregs (nTregs) that allow for the practical employment
      of this cellular therapy in the clinic. Our central hypothesis is that sufficient human nTreg
      can be expanded ex vivo and used to both prevent renal transplant rejection and facilitate
      the reduction and subsequent withdrawal of drug-based immunosuppression. This study will
      allow for us to define the safety of Treg adoptive cellular transfer (TRACT) in living donor
      renal transplant recipients that draws upon our extensive preclinical experience with
      expanded Tregs, as well as our recognized clinical expertise with designing immunosuppressive
      regimens compatible with this type of therapeutic cell transfer.
    

Detailed description: 
      Transplantation is the treatment of choice for most causes of end stage renal disease.(1, 2)
      However, without some modification of the recipient's immune system all allografts succumb to
      rejection. To prevent this, patients must take immunosuppressive drugs for life, generally a
      combination of steroids, a calcineurin inhibitor (CNI), such as cyclosporine or tacrolimus,
      and an antiproliferative agent (azathioprine, mycophenolate mofetil or sirolimus).(3-6)
      Induction with a brief course of an anti-T lymphocyte antibody preparation (daclizumab,
      basiliximab, muromonab, alemtuzumab, polyclonal anti-thymocyte globulin) is also used in
      approximately 70% of U.S. transplant centers.

      Dependence on immunosuppression tempers the substantial benefit obtained from transplantation
      (1-13). The typical regimens are relatively complex and expensive. More importantly, they
      increase the risk of opportunistic infection and malignancy, and have many non-immune side
      effects that hamper their tolerability. Specifically, CNIs are nephrotoxic, a side effect of
      significant concern in renal transplantation. Steroids exacerbate osteoporosis and
      hyperlipidemia, and cause avascular osteonecrosis. Both classes of agent worsen glucose
      tolerance and hypertension, and are associated with cosmetic effects causing non-compliance.
      As such, methods of transplantation that lessen the dependence on chronic immunosuppression
      stand to reduce the risk and expense of transplantation. They must, however, also prevent
      rejection. Development of alternate therapies that help to minimize the need for lifelong
      immunosuppression, or eliminate entirely the need for drugs through the induction of
      tolerance, are therefore of great interest.

      Regulatory CD4+CD25+ T cells (Treg) derived from the thymus and/or peripheral tissues have
      been demonstrated to broadly control T cell reactivity (14). Importantly, Tregs have been
      shown to control immune responsiveness to alloantigens and significantly contribute to
      operational tolerance in transplantation models (15, 16). However, there have been limited
      efforts to harness the therapeutic potential of directly isolated CD4+CD25+ Treg cells for
      controlling graft rejection and inducing transplantation tolerance, such as for kidney
      transplants. In order for CD4+CD25+ Treg cells to be used as a clinical treatment, the
      following cell properties could be necessary: ex vivo generation of sufficient numbers of
      cells, migration in vivo to sites of antigenic reactivity, ability to suppress rejection in
      an alloantigen-specific manner, and survival/expansion after infusion for a critical, but
      currently unknown, period of time. Our published work and that of other investigators has
      demonstrated 1) the feasibility of expanding Treg ex vivo, 2) the ability of these cells to
      downregulate allogeneic immune responses in vitro, and 3) the efficacy of Treg for prevention
      of allograft rejection in animal models (15,16). We have developed strategies for the ex vivo
      expansion of naturally occurring human Tregs (nTregs) that allow for the practical employment
      of this cellular therapy in the clinic. Our central hypothesis is that sufficient human nTreg
      can be expanded ex vivo and used to both prevent renal transplant rejection and facilitate
      the reduction and subsequent withdrawal of drug-based immunosuppression. This study will
      allow for us to define the safety of Treg adoptive cellular transfer (TRACT) in living donor
      renal transplant recipients that draws upon our extensive preclinical experience with
      expanded Tregs, as well as our recognized clinical expertise with designing immunosuppressive
      regimens compatible with this type of therapeutic cell transfer.
    

Intervention name(s): Expanded Tregs
Intervention type(s): Drug
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Kidney transplant; Regulatory T cells; Leukopheresis; Immune cells; Stem Cells; Tolerance