Autologous Ex Vivo Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency-I Achieves Durable Immune Reconstitution and Reduction of Infection-Related Morbidity: Updated 3.5-5.5-Year Results from a Phase I/II Study
Jul 2026· Journal of Human Immunity· Vol 2· 0 citations
TL;DR
Autologous HSC gene therapy is supported as an effective alternative to alloHSCT with a favorable risk-benefit profile for severe LAD-I, and markedly lower annualized incidences of prespecified serious infections, infection-related hospitalizations, and prolonged infection-related hospitalizations after RP-L201 treatment relative to pre-treatment incidences.
Abstract
Severe leukocyte adhesion deficiency-I (LAD-I) is caused by biallelic deleterious variants in ITGB2, resulting in <2% CD18 expression and impaired leukocyte extravasation, particularly neutrophils. Affected infants and children experience recurrent, life-threatening bacterial and fungal infections, poor wound healing, and significant mortality in the absence of allogeneic hematopoietic stem cell transplantation (alloHSCT). Although alloHSCT can be curative, many patients lack suitable donors and remain at risk for graft-versus-host disease (GvHD), graft failure, and transplant-related morbidity and mortality. Treatment with a durable autologous hematopoietic stem cell (HSC) gene therapy was developed to address these limitations.
To evaluate the long-term safety and efficacy of RP-L201 (marnetegragene autotemcel), an autologous CD34+ HSC gene therapy using a Chim-CD18-WPRE lentiviral vector incorporating ITGB2, we investigated restoration of CD18 expression, normalization of neutrophil function, and reduction in infection-related morbidity in children with severe LAD-I.
Children ≥3 months old with severe LAD-I were enrolled in the phase I/II study (NCT03812263). CD34+ cells obtained via G-CSF/plerixafor mobilization and apheresis were transduced ex vivo with RP-L201 and infused following therapeutic drug-monitored myeloablative conditioning. Endpoints included survival without alloHSCT, restoration of peripheral blood (PB) polymorphonuclear (PMN) CD18 expression, peripheral blood mononuclear cell (PBMC) vector copy number (VCN), integration site analysis, resolution of baseline leukocytosis, and incidence of infection-related hospitalizations. All treated patients entered the long-term follow-up (LTFU) study (NCT06282432).
Nine patients (age 9.8-117.4 months at infusion) received RP-L201 and were followed for a median (range) of 50.92 (42.6-67.9) months as of the June 18, 2025, LTFU data cut. AlloHSCT-free survival was 100% with no cases of graft failure. PBMC VCN/cell rose to 0.42-2.4 at month 3 and remained stable through month 12 (mean 1.73) with persistent long-term VCN levels across months 42-60. All patients achieved sustained PB PMN CD18 expression within or approaching the target levels, maintained through >3.5 years post-infusion. Longer-term results demonstrate markedly lower annualized incidences of prespecified serious infections, infection-related hospitalizations, and prolonged infection-related hospitalizations after RP-L201 treatment relative to pre-treatment incidences. No new skin or oral infections occurred in the LTFU period. RP-L201 was well-tolerated; no RP-L201-related adverse events occurred. Integration site analyses demonstrated polyclonal integration patterns without dominant or expanding clones.
RP-L201 conferred durable engraftment, sustained CD18 restoration, and significant reductions in infection-related morbidity in nine children with severe LAD-I, with at least 3.5 years of follow-up. All nine patients are alive without alloHSCT. There were no RP-L201-related adverse events. These updated results support autologous HSC gene therapy as an effective alternative to alloHSCT with a favorable risk-benefit profile for severe LAD-I.
It is concluded from preliminary data that gene therapy using BE HSPCs appear very promising for achieving an earlier and more robust multi-lineage immune reconstitution in adult patients using BE HSPCs.
S. S. de Ravin, Michelle Ma, Yuzhi Yin et al.· Journal of Human Immunity· 0 citations
Graft-versus-host disease (GVHD) remains a primary cause of morbidity and mortality post-allogeneic hematopoietic stem cell transplantation (allo-HSCT), driven by donor T cells’ dysregulated inflammation against host tissues. This limits survival and underscores the need for therapies that curb GVHD while preserving graft-versus-tumor (GVT) effects. Innate-like T cell subsets, including MAIT, NKT, and Vγ2 γδ T cells correlate with milder GVHD. These share the BTB-ZF transcription factor PLZF (Zbtb16), a master regulator of innate-like programming. Building on our finding that ectopic PLZF imparts innate-like traits to conventional αβ T cells, we tested if PLZF-overexpressing donor T cells suppress GVHD in vivo.
In a B6→BALB/c acute GVHD model, lethally irradiated BALB/c recipients received bone marrow plus purified CD4+/CD8+ T cells from C57BL/6 donors, transduced with retroviral PLZF or empty vector (EV) control (n = 15/group). Mice were monitored daily for survival, clinical scores, and weight loss.
In mouse models of acute GVHD (B6→BALB/c), adoptive transfer of retrovirally transduced, PLZF-overexpressing conventional T cells markedly delayed disease onset and enhanced survival relative to empty vector-transduced controls. Mechanistically, PLZF-overexpressing conventional T cell promoted expansion of regulatory T cell (Treg) populations, thereby driving a phenotypic shift toward innate-like suppression of alloimmunity.
These results affirm PLZF overexpression as a viable, programmable approach for GVHD prophylaxis, poised for clinical advancement. Through innate-like T cell reprogramming, this strategy holds promise for revolutionizing allo-HSCT by decoupling immune tolerance from antitumor immunity. Current investigations are evaluating PLZF-overexpressing conventional T cell preservation of graft versus tumor (GVT) activity against leukemia and extending these findings to humanized models.
NJ PHORCE
Transplantation Immunology (TRAN)
Jake Cox, Dhruti Patel, Steven Montecinos Montes et al.· Journal of Immunology· 0 citations
Introduction. Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a life-threatening complication, with an incidence of 5–20% in pediatric patients with acute leukemia. Macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH) represents one of the most aggressive triggers of GF, being closely associated with cytokine storm, multiple organ dysfunction, and high transplant-related mortality. In the setting of primary or secondary GF, a second allo-HSCT remains the only potentially curative treatment option; however, performing it against a background of hyperinflammation carries substantial risks of fatal complications and recurrent non-engraftment.
The aim of the study – to evaluate factors influencing the rates of non-engraftment, overall survival, and relapse-free survival following second allo-HSCT in pediatric patients with acute leukemia who suffered primary or secondary GF after their first allo-HSCT.
Materials and methods. This retrospective single-center study included 44 pediatric patients (median age 9.4 years) with acute myeloid leukemia (n = 11), acute lymphoblastic leukemia (n = 28), and myeloproliferative neoplasms (n = 5). Primary GF was diagnosed in 65.9% of patients, while secondary GF/rejection occurred in 34.1%. Key triggers of MAS/sHLH included viral infections (Epstein–Barr virus, cytomegalovirus, human herpes virus 6, parvovirus B19), bacterial/fungal complications, and cytokine release syndrome. Prior to the second HSCT, conditioning regimens consisted of reduced-intensity conditioning in 79.5% and anti-thymocyte globulin-based conditioning in 20.5%; a subset of patients received anti-cytokine therapy. A switch to a different HLA-matched donor was performed in 47.7% of cases. The median follow-up was 3 years.
Results. The cumulative incidence of engraftment was 73% (median time to neutrophil recovery – 15 days). One-year overall survival was 64% (95% confidence interval (CI) 48–76), relapse-free survival was 57% (95% CI 41–70), and non-relapse mortality was 34% (95% CI 20–48). The main causes of death were infectious complications (n = 7), hepatic veno-occlusive disease/sinusoidal obstruction syndrome/transplant-associated thrombotic microangiopathy (n = 6), acute respiratory distress syndrome (n = 3), and cerebrovascular accident (n = 2). The incidence of grade II–IV acute GVHD was 61%, with grade III–IV occurring in 36%. HLA donor switch, stem cell source, and conditioning regimen, including anti-thymocyte globulin use, did not demonstrate a statistically significant impact on overall survival.
Conclusion. A second allo-HSCT in pediatric patients with GF complicated by MAS/sHLH demonstrates acceptable engraftment and survival outcomes, remaining the only available option for long-term disease control. The high incidence of early immunological complications and non-relapse mortality necessitates exactly pre-transplant optimization, performing of weekly serum ferritin and inflammatory marker monitoring, and morphological confirmation of hemophagocytosis during the early post-transplant period (days +14 to +21), particularly in the absence of hematopoietic recovery. Optimization of targeted anti-cytokine therapy and intensified prophylaxis/management of infectious complications represent priority strategies to reduce transplant-related mortality.
P. Kozhokar, O. Yudintseva, O. Paina et al.· Pediatric Hematology/Oncolog...· 0 citations
Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the leading cause of treatment failure in acute myeloid leukemia (AML), particularly in genetically adverse subtypes. Although prophylactic donor lymphocyte infusion (DLI) may augment graft-versus-leukemia effects, its stand-alone efficacy is suboptimal, necessitating rational combination approaches. Limited case reports have suggested potential clinical benefits of gemtuzumab ozogamicin (GO) in combination with DLI as salvage therapy for post-transplant relapse; however, its role in prophylactic maintenance has not been determined. We report a 29-year-old woman with chemo-refractory AML harboring t(1;3)(p36.3;q21) who relapsed approximately 3 months after her first allo-HSCT. She underwent a second haploidentical allo-HSCT without achieving remission beforehand. Given the extremely high risk of relapse, she received immune-directed maintenance with low-dose GO (3 mg/m2 on days 98 and 140 post-transplant) followed by dose-escalated DLI (six monthly infusions starting on day 374). Although the patient developed chronic graft-versus-host disease, including pulmonary involvement (NIH lung score 2), it remained clinically manageable. She maintained molecular complete remission for more than 6 years. Our case suggests that sequential low-dose GO followed by stepwise DLI may support durable remission when used as a post-transplant maintenance strategy in chemo-refractory AML with adverse cytogenetics, such as t(1;3)(p36.3;q21). This maintenance approach warrants further investigation to clarify feasibility and safety.
Fumihiko Ouchi, Y. Najima, K. Haraguchi et al.· Frontiers in Immunology· 0 citations
Gastrointestinal acute graft-versus-host disease (GI aGVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT), and early risk identification and intervention are essential for improving outcomes. Mucosal-associated invariant T (MAIT) cells are mucosa-enriched unconventional T cells with major histocompatibility complex class I-related protein 1 (MR1)-restricted, major histocompatibility complex (MHC)-independent recognition, suggesting a potentially reduced risk of alloreactivity. Our previous work showed that higher graft MAIT-cell levels were associated with improved post-transplant MAIT-cell reconstitution and a lower incidence of GI aGVHD. Single-cell ribonucleic acid (RNA) sequencing (sc-RNA-seq) and murine models revealed their functional heterogeneity in immune regulation, tissue repair and chemotaxis-supporting their role as both biomarkers and therapeutic targets. In this prospective study, spectral flow cytometry was used to characterize MAIT-cell phenotypes in peripheral blood stem cell grafts. higher graft MAIT-cell abundance was associated with more robust early post-transplant MAIT-cell reconstitution and a lower risk of GI aGVHD. A three-marker predictive panel based on MAIT-cell functional markers (C-C chemokine receptor type 2 [CCR2], interleukin-4 [IL-4], interleukin-17A [IL-17A]) achieved an area under the receiver operating characteristic curve (AUC) of 0.80, increasing to 0.85 after adjustment for clinical covariates. These findings identify graft-derived MAIT cells as a predictive immune-associated biomarker for GI aGVHD, enabling pre-transplant risk stratification and supporting precision prevention strategies. Trial registration: ChiCTR2500095349.
Mengge Gao, Rong Cheng, Kong Jun et al.· British Journal of Haematolo...· 0 citations
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment primarily for hematological malignancies. Infections, relapse, and graft versus host disease (GvHD) are some of the most common adverse events following HSCT. We aimed to evaluate whether the lymphocyte function of the stem cell graft was associated with these events.
STUDY DESIGN AND METHODS
We included peripheral blood stem cell (PBSC) grafts from 53 donors to HSCT recipients. The grafts' lymphocyte function was assessed by in vitro blast formation, expression of activation markers, and cytokine production upon stimulation. The cellular composition of the grafts was determined with flow cytometry. Results were compared with the incidence of infections, GvHD, relapse, and survival in the HSCT recipients.
RESULTS
We found an association between lower graft T cell response upon mitogen or superantigen stimulation and cytomegalovirus reactivation (p = .013 and p = .0028). Recipients of grafts with an above-median programmed death-1 (PD-1) expression on CD8+ T cell blasts had a higher incidence of relapse and lower overall survival (p = .02). Both findings remained significant in the multivariable analysis.
DISCUSSION
Measurement of the lymphocyte response upon mitogen stimulation of PBSC grafts might provide beneficial knowledge of graft-related factors that contribute to the incidence of complications after HSCT.
Anna Söderström, Tengyu Wang, J. Törlén et al.· Transfusion· 0 citations
