This open-label, proof-of-principle two center cohort study will evaluate the ability of autologous hematopoietic stem cell transplantation to induce tolerance in recipients of deceased or live donor liver transplants (ASCOTT). A maximum of 10 participants will be entered at a minimum of 3 months post liver transplant. The participants will undergo autologous hematopoietic stem cell transplants (HSCT) to "re-educate" their immune systems to accept the graft without the need for long term immunosuppression (tolerance).
Although short-term results for liver transplantation are excellent, the need for immunosuppression limits quality of life and long-term survival. Investigators plan to examine the utility and safety of autologous hematopoietic stem cell transplantation (HSCT) to allow withdrawal of immunosuppression in 10 liver transplant recipients who are at a high risk of developing recurrent liver damage from repeated bouts of rejection, or recurrent disease or who have a high likelihood of developing serious medical complications from complications of immune suppression. Hematopoietic stem cells will be mobilized, purified and cryopreserved. Following a chemotherapy and Anti-thymocyte Globulin (ATG) based-regimen for immune ablation, the purified stem cells will be thawed and infused back into participants (autologous hematopoietic stem cell transplant - HSCT). Participants will be converted to everolimus, a mammalian target of rapamycin inhibitor (mTORi), which will be continued for 6 months and then withdrawn based on histologic evidence of graft acceptance. Participants will be followed closely for a total of 24 months for any biochemical and histologic evidence of tolerance or rejection. Re-vaccination to common viral and bacterial antigens will be undertaken as required using a standard protocol for recipients of a hematopoietic stem cell transplant (HSCT).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
Step 1: Participants will receive intravenous chemotherapy and cytokine-based treatment for mobilization of hematopoietic stem cells (HSC) into the circulation, followed by collection using peripheral vein leukopheresis. The HSC graft product will undergo ex vivo purification with CD34 selection using Miltenyil CliniMACS and cryopreserved. Step 2: Intravenous busulphan, cyclophosphamide and anti-thymocyte globulin will be administered to participants to achieve immune ablation prior to the infusion of the participants' own thawed HSC graft product (HSC transplant). Routine supportive measures will be employed during the recovery from the chemotherapy and HSCT. Participants' immune suppression will be stopped at the time of immunoablative therapy and will be switched to everolimus which will be discontinued at 6 months post HSCT.
The Ottawa Hopital
Ottawa, Ontario, Canada
Multi-Organ Transplant Program, Toronto General Hospital
Toronto, Ontario, Canada
Number of patients who develop tolerance post autologous HSCT
Number of patients who develop tolerance at 24 months post HSCT as defined clinically and histologically in the absence of any immunosuppression in liver transplant recipients.
Time frame: 24 months post HSCT
HSCT mortality
Time frame: 2 years post HSCT
HSCT related morbidity
Time frame: at 2 years post HSCT
Rate of immune reconstitution
Time frame: at 2 years post HSCT
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
5