GMP-manufactured allogeneic human t lymphoid progenitors (HTLP) promote early and sustained T-cell recovery after CD34+-selected haploidentical HSCT in SCID patients : Final results of the htlp-SCID study
Year: 2025
Type: conference-abstract
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.
Source: Blood
Authors: Jean-Sebastien Diana, Elisa Magrin, Martin Castelle, Steicy Sobrino, Eleonore Mathe, Benjamin Fournier, Olivier Negre, Aurelie Bauquet, Eden Schwartz, Ugo Chartral, Naim Bouazza, Axelle Maulet, Alice Girardot, Juliette Olivre, Aurélie Gabrion, Jeremie Rosain, Capucine Picard, Chantal Lagresle-Peyrou, Aurore Touzart, Ludovic Lhermitte, Jean-Marc Treluyer, Benedicte Neven, Isabelle André, Despina Moshous, Marina Cavazzana
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417011034
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