The goal of this clinical trial is to evaluate the safety and feasibility of inducing hematopoietic mixed chimerism to promote immune tolerance and potentially reduce the need for lifelong immunosuppression in pediatric and adult patients undergoing solid organ transplantation (SOT), including kidney, lung, and multivisceral transplants.
The main questions it aims to answer are:
* Is it safe to infuse a naïve T cell-depleted hematopoietic graft along with memory T-lymphocytes after SOT? * Can this approach support immune tolerance and reduce the incidence of rejection and infection without long-term immunosuppression?
Participants will:
* Undergo a solid organ transplant from a living or deceased donor. * Wait through a stabilization period to ensure resolution of early transplant-related complications. * Receive low-dose preconditioning (TLI and thymic irradiation) to prepare for hematopoietic stem cell transplantation. * Be infused with a graft containing CD34+ progenitor cells, memory T cells (CD45RO+), and no naïve T cells (CD45RA+); in some cases, NK cells may also be included. * Be followed for graft survival, immune tolerance, infection rates, and adverse events through regular clinical and immune monitoring visits.
Pediatric patients (<18 years old) who are candidates to receive intestinal or lung transplantation (before SOT).
Pediatric (<18 years old) or adult patients (≥18 years old) who are either candidates for renal transplantation or have already undergone renal transplantation and remain candidates for subsequent HSCT.
Patients who provide informed consent (or their legal guardians in the case of minors) before any study-related procedures.
Recipients should have no active infectious disease or other medical condition that would contraindicate the combined transplantation procedure, as determined by the investigational team.
Recipients with existing bone marrow disorders or those receiving medications known to adversely affect bone marrow function.
Patients with advanced organ dysfunction (hepatic, cardiac, or pulmonary) incompatible with successful combined transplantation.
Patients with active or uncontrolled autoimmune conditions that may interfere with transplantation and the induction of chimerism.
Patients with known allergies to medications or products required for conditioning or transplantation.
Single group
Investigational cellular therapy consisting on a HSCT using a graft enriched in CD34+, depleted of naïve T-lymphocytes and supplemented with memory lymphocytes
Biological/VaccineInfusion Schedule 1. Primary Infusion: the enriched graft, containing the CD34+ progenitors and depleted naïve T cells, will be infused after the patient has undergone conditioning therapy. 2. In the case of haploidentical donors, an additional NK cell infusion will be administered whenever possible around day 7 post-transplant from a non-mobilized apheresis collection, aiming to enhance graft tolerance and prevente HHV6 disease. 3. Post-Transplant Memory T cell Infusions: beginning on days 15 and 30, and then administered monthly up to a maximum of one year or until the supply is depleted, memory T cells will be infused. Conditioning Regimen Prior to HSCT, all patients will undergo a low-intensity conditioning regimen designed to allow engraftment of the donor cells while minimizing toxicity: 1. Total Lymphoid Irradiation (TLI): 8 Gy of total lymphoid irradiation will be administered. 2. Fludarabine: a total dose of 120 mg/m², spread over 4 days (-6 to -3 before transplant), will serv
Incidence of adverse events related to the investigational intervention.
Safety and tolerability will be evaluated based on the incidence, nature and and severity of adverse events during study period. (clinical and laboratory).
Feasibility of cell collection, processing and administration.
* Proportion (%) of participants in which we are able to obtain naïve T cell depleted graft and memory T cells, from alive and deceased donors. * Prorportion (%) of participants in which we are able to obtain naïve T cell depleted graft and memory T cells from deceased donors. * Proportion (%) of patients who are able to proceed to haematopoietic stem cell therapy within 3 months following solid organ transplantation.
Mixed hematopoietic chimerism measurement.
Proportion (%) of patients presenting mixed hematopoietic chimerism ≥ 100 days, macrochimerism (\>5%) ≥ 100 days, macrochimerism ≥ 30 days and microchimerism (\< 5%) ≥ 30 days.
Donor-Specific T Cell Clone Depletion
Proportion (%) of patients demonstrating donor's alloreactive clones depletion by high resolution TCR sequencing one year post haematopoietic stem cell therapy and thereafter.
Organ Rejection Rate
Proportion (%) of patients experiencing organ rejection 1 year after investigational therapy administration.
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Francisco Hernández Oliveros
Lead sponsor
Hospital Universitario La Paz
Sponsor institution
