Phase I Trial on the Safety of Delayed Infusion of a Naïve T Cell-Depleted Hematopoietic Graft With Memory T Cells in Solid Organ Transplant Recipients

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

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.

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.

The infused cell product is carefully designed:

• It includes CD34+ blood stem cells, which help rebuild the patient's immune and blood systems.
• It removes "naïve" T cells (CD45RA+), which are known to cause GVHD.
• It includes "memory" T cells (CD45RO+), which support immune recovery and protection against infections.

In some cases, natural killer cells CD56+ may also be included to help protect against viruses and support tolerance-especially when the donor is haploidentical.

The way the cells are collected depends on whether the donor is living or deceased. For living donors, peripheral blood stem cells are collected. For deceased donors, the bone marrow is used.

This trial is based on encouraging results from earlier studies and aims to show that this strategy is safe and feasible. If successful, the benefits could be wide-ranging:

• Less dependence on lifelong immunosuppressive medications
• Lower risk of chronic rejection of the transplanted organ
• Fewer life-threatening infections
• Improved quality of life, especially for children and young adults
• Increased availability of transplantable organs by improving outcomes and reducing re-transplantation needs
• Lower healthcare costs due to fewer complications, hospitalizations, and medications

The study will also track how well the patient's body accepts the transplanted organ over time and whether true immune tolerance is achieved. This will be monitored by looking at immune markers in the blood and through regular clinical follow-ups.

This approach could be especially helpful for pediatric patients, who face unique challenges, such as difficulty adhering to lifelong medication plans and a higher risk of needing multiple transplants. It may also help adult patients at high risk of rejection, or those who have already had complications with previous transplants.

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.