Abstract
Introduction : Alternative donor Hematopoietic Stem Cell Transplantation (HSCT) is often associated with delayed immune reconstitution compared to matched donors, especially in recipients of CD34+-selected haploidentical transplants. We previously demonstrated in preclinical models that the administration of CD7+ T cell progenitors, produced ex vivo, promotes thymic regeneration and accelerates polyclonal T-cell production. These findings supported the clinical development of human allogenic T lymphoid progenitors (HTLP) to accelerate post-HSCT immune reconstitution in transplanted patients for Severe Combined Immune Deficiencies (SCID). Here, we present the final results of the HTLP-Necker study.
Method : We conducted a first-in-human, open-label clinical trial (EudraCT 2019-004883-23) to evaluate the safety and efficacy of HTLP administered after haplo CD34+-selected allogeneic HSCT in patients with SCID. Fresh HTLP were infused between days +7 or after cryopreservation at +14 post-HSCT, following ATG clearance. The Investigational Medicinal Product was manufactured under GMP-conditions from donor CD34+ cells and consisted of CD7+ CD3– lymphoid progenitors. Key outcomes included safety, engraftment, T-cell recovery, thymic activity, and infection rates.
Results: Four SCID patients received HTLP following CD34+-selected HSCT. HTLP products showed robust differentiation (median 79.7% CD7+ CD3–) and expansion (median 14.7-fold). Infused doses ranged from 0.1 to 0.3 ×10⁶ CD7+CD3-cells/kg, with minimal residual CD3+ cells (<11.2/kg). After a median follow-up of 63 months (range, 1.5-156 months), no infusion-related toxicity or chromosomal instability was observed. One patient died from severe veno-occlusive disease (VOD) on day 53, unrelated to HTLP. Two out of three patients achieved successful primary engraftment, no grade ≥2 acute Graft Versus Host Disease (GVHD) occurred, and CD3+ CD4+ TCRαβ+ T cells exceeded 50/μL by month four. One patient with residual maternal T-cells experienced a temporary skin flare linked to maternal T-cell alloreactivity, as confirmed by chimerism studies. The progressive acquisition of allogeneic T chimerism is associated with the resolution of maternal-fetal GVH symptoms. We performed short and long-term analysis of intrathymic activity (TREC, RTE quantification, and thymic ultrasound). Both patients experienced effective long-term T cell reconstitution, with 1185 and 1672 T-CD4/mm³, respectively, and 65% of RTE at M24. No viral reactivations or disease relapses were reported. To contextualize these results, we performed a Bayesian comparative analysis of CD4+ T-cell reconstitution against age- and genotype-matched SCID patients receiving standard haploidentical CD34+-selected HSCT. HTLP-treated patients showed earlier and stronger CD4+ recovery. In addition, TCRβ repertoire analysis revealed greater diversity compared to historical controls.
Conclusion : HTLP infusion post-HSCT is feasible and safe, with no infusion-related toxicity or severe GVHD. Longitudinal data demonstrate early, robust, and sustained T-cell reconstitution, supported by intrathymic activity. HTLPs may represent a promising strategy to enhance immune recovery in patients undergoing alternative donor transplantation.
