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

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.

• Feasibility of cell collection, processing and administration. [Срок оценки: From enrollment to 3 months after solid organ transplantation]
• Mixed hematopoietic chimerism measurement. [Срок оценки: From therapy administration to 30 days and 100 days after investigational therapy administration]
• Donor-Specific T Cell Clone Depletion [Срок оценки: One year post haematopoietic stem cell therapy and thereafter.]
• Organ Rejection Rate [Срок оценки: From investigational therapy administration to 1 year after]
• Graft Survival and Failure Rates [Срок оценки: 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. [Срок оценки: 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. [Срок оценки: 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 [Срок оценки: Day 100 post haematopoietic stem cell therapy.]
• Immune reconstitution in patients receiving investigational cell therapy [Срок оценки: From enrollment to end of follow-up at 2 years after cell therapy administration]
• Development of immune tolerance in transplant recipients [Срок оценки: One-year post haematopoietic stem cell therapy and thereafter.]
• Recipient's laboratory hyporesponsiveness towards the graft [Срок оценки: One-year post haematopoietic stem cell therapy and thereafter.]
• Recipient's competence against third party donors [Срок оценки: One-year post haematopoietic stem cell therapy and thereafter.]