Naive T cell-depleted hematopoietic stem cell transplantation to minimize immunosuppression after solid organ...

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).