Naive T cell-depleted hematopoietic stem cell transplantation to minimize immunosuppression after solid organ transplantation: case report

Solid organ transplantation (SOT) outcomes remain suboptimal due to graft rejection, drug-related complications and comorbidities. Hematopoietic stem cell transplantation (HSCT) has been explored to induce chimerism and tolerance, reducing reliance on immunosuppression. We report two patients who, post-SOT, received non-myeloablative conditioning followed by a naïve T-cell–depleted HSCT and memory T-cell (CD45RA⁻) donor lymphocyte infusions under a compassionate use program. Mixed lymphocyte reaction (MLR) experiments performed 41 (Patient #1) and 31 (Patient #2) months after SOT/HSCT and TCRβ deep Illumina sequencing, together with clonotype frequency analysis, were used to identify donor-reactive T-cell clonotypes. Both patients were maintained in minimal immunosuppression with no signs of rejection more than 5 years after the SOT/HSCT. Recipient cells resulted hyporesponsive to donor and third-party cells, yet retained reactivity to CMV infection. TCRβ profiling provided an overview of the lymphocyte subpopulations before and after transplantation. Donor-reactive clonotypes potentially associated with rejection were identified pre-HSCT and monitored after this procedure. Our clinical strategy is a feasible, safe approach to induce transient mixed chimerism and may support minimization of immunosuppression following SOT. Despite considerable heterogeneity between patients - affected organ, donor source (deceased/living), and HLA compatibility (fully mismatched/matched sibling) -, we consider our findings to provide a valuable foundation for development of a clinical trial recently started at our hospital: A phase I, single-center, open-label trial to assess safety and tolerability of delayed infusion of a naïve T-cell-depleted hematopoietic graft and memory T-lymphocytes in recipients of solid organ transplantation (NCT06997471). Organ transplants can save lives, but people usually need to take medicines for the rest of their lives to stop their body from rejecting the new organ. These medicines can cause serious side effects. In this study, we describe two patients who received an organ transplant and, shortly afterwards, a blood stem cell transplant from the same donor. The treatment used a gentle preparation that avoided intensive chemotherapy. The goal was to help the body’s immune system accept the new organ while reducing the need for anti-rejection medicines. We also identified and tracked the immune cells that react against the donor over time. Several years later, both patients remain stable, have no signs of organ rejection, and only need very low doses of anti-rejection medicines. These encouraging results have led to a new study at our hospital to test this approach in more patients. If successful, it could improve quality of life for future transplant recipients. Pérez-Martínez et al., describe two solid organ transplant recipients treated with non-myeloablative conditioning followed by naïve T-cell-depleted hematopoietic stem cell transplantation and donor memory T-cell infusions, and use mixed lymphocyte reactions with TCRβ sequencing to track donor-reactive T-cell clonotypes. Both patients remain rejection-free on minimal immunosuppression more than five years after transplantation, exhibit transient mixed chimerism and donor hyporesponsiveness while retaining antiviral immunity, supporting the feasibility of testing this approach in a larger clinical study.