A Phase I, Single-Center, Open-Label Trial to Assess the Safety and Tolerability of Delayed Infusion of a Naïve T Cell Depleted Hematopoietic Graft and Memory T-lymphocytes in Recipients of Solid Organ Transplantation
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Enrollment
- 10
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events related to the investigational intervention.
Study Overview
Brief Summary
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.
Detailed Description
This clinical trial is exploring a new way to help patients who receive a solid organ transplant-such as a kidney, lung, or intestine-live longer and healthier lives with fewer side effects from medication. Today, most transplant recipients must take strong immune-suppressing drugs every day to prevent their bodies from rejecting the new organ. While these drugs are essential, they can lead to serious complications over time, such as infections, and even damage to the transplanted organ itself.
The goal of this study is to test a promising strategy that may help the body naturally accept the transplanted organ, reducing or potentially eliminating the need for long-term immunosuppressive drugs. This approach involves a technique called mixed hematopoietic chimerism, which means that the patient's body receives a mix of immune cells from both themselves and the organ donor. When successful, this blend of immune systems can lead to immune tolerance, allowing the transplanted organ to function without being attacked by the patient's immune system.
This is a Phase I, single-center, open-label clinical trial, which means it is an early-stage study focused primarily on evaluating safety. The trial will enroll 10 patients who are either scheduled to receive a solid organ transplant (SOT) or have recently undergone one, depending on the type of organ and donor availability.
After a transplant, each patient must go through a stabilization period, allowing time for any immediate post-surgical complications to improve. Once stabilized, the patient will receive a specially prepared infusion of blood-forming (hematopoietic) stem cells from their organ donor. This process is known as hematopoietic stem cell transplantation (HSCT).
Before this infusion, patients will undergo low-dose preconditioning using total lymphoid irradiation (TLI) and thymic irradiation. These treatments prepare the body to accept the donor's cells without causing major immune damage, and they aim to lower the risk of complications like graft-versus-host disease (GVHD)-a serious condition where donor immune cells attack the patient's tissues.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Prevention
- Masking
- None
Eligibility Criteria
- Ages
- 0 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
- •Patients with severe psychiatric or cognitive disorders that may interfere with adherence to study instructions or postoperative care.
- •Patients currently enrolled in another clinical trial that could interfere with the outcomes or safety of this study.
- •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
- •Any other condition that, in the opinion if the Investigator, may interfere with the efficacy and/or safety evaluation of the trial.
Arms & Interventions
HSCT using a graft enriched in CD34+ hematopoietic progenitor cells
The study intervention involves a HSCT using a graft enriched in CD34+ hematopoietic progenitor cells. This graft will be specifically engineered through depletion of naïve T-lymphocytes (CD45RA+) and patients will be supplemented with memory lymphocytes to support immune reconstitution and promote tolerance. The source of the hematopoietic stem cells (HSCs) will vary depending on whether the donor is a living related donor (HLA-identical or haploidentical) or a deceased donor.
Graft Composition and Cell Doses
- CD34+ cells: < 1 x 107/kg will be intravenously infused as the primary source of hematopoietic progenitors.
- Memory T-lymphocytes (CD45RO+): < 3 x 107/kg will be administered. Naïve T-lymphocytes (CD45RA+) remaining in the memory fraction will always be <1 x 104/kg, to minimize the risk of GVHD while supporting immune surveillance.
- Only in haploidentical participants: NK cells (CD56+): < 5 x 107/kg to promote graft tolerance and target residual malignant cells.
Intervention: Investigational cellular therapy consisting on a HSCT using a graft enriched in CD34+, depleted of naïve T-lymphocytes and supplemented with memory lymphocytes (Biological)
Outcomes
Primary Outcomes
Incidence of adverse events related to the investigational intervention.
Time Frame: From enrollment to end of follow-up at 2 years after cell therapy administration
Safety and tolerability will be evaluated based on the incidence, nature and and severity of adverse events during study period. (clinical and laboratory).
Secondary Outcomes
- Feasibility of cell collection, processing and administration.(From enrollment to 3 months after solid organ transplantation)
- Mixed hematopoietic chimerism measurement.(From therapy administration to 30 days and 100 days after investigational therapy administration)
- Donor-Specific T Cell Clone Depletion(One year post haematopoietic stem cell therapy and thereafter.)
- Organ Rejection Rate(From investigational therapy administration to 1 year after)
- Graft Survival and Failure Rates(From enrollment to end of follow-up at 2 years after cell therapy administration)
- occurence of GVHD in patients receiving delayed infusion of the investigational celular therapy after solid organ transplantation.(From enrollment to end of follow-up at 2 years after cell therapy administration)
- Occurrence of infections in patients receiving delayed infusion of the investigational celular therapy after solid organ transplantation.(From enrollment to end of follow-up at 2 years after cell therapy administration)
- Immune reconstitution in patients receiving delayed infusion of the investigational celular therapy after solid organ transplantation(Day 100 post haematopoietic stem cell therapy.)
- Immune reconstitution in patients receiving investigational cell therapy(From enrollment to end of follow-up at 2 years after cell therapy administration)
- Development of immune tolerance in transplant recipients(One-year post haematopoietic stem cell therapy and thereafter.)
- Recipient's laboratory hyporesponsiveness towards the graft(One-year post haematopoietic stem cell therapy and thereafter.)
- Recipient's competence against third party donors(One-year post haematopoietic stem cell therapy and thereafter.)
- Recipient's competence against virus(One-year post haematopoietic stem cell therapy and thereafter.)
- Mortality after investigational therapy adminitration.(From enrollment to one year after investigational therapy administration)
Investigators
Francisco Hernández Oliveros
Physician in the Department of Pediatric Surgery. Head of the Pediatric Transplant Section.
Hospital Universitario La Paz