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LENTIVIRAL HEMATOPOIETIC STEM AND PROGENITOR CELL GENE THERAPY FOR WISKOTT-ALDRICH SYNDROME: SAFETY AND CLINICAL BENEFIT IN 23 PATIENTS UP TO 10.5 YEARS OF FOLLOW-UP
Abstract
Background and Aims
Wiskott-Aldrich Syndrome (WAS) can be treated with allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT outcome is hampered by limited donor availability and potential complications, with higher risks in older subjects. Gene therapy (GT) is currently being studied as an alternative treatment.
Methods
OTL-103 is an investigational autologous hematopoietic stem and progenitor cell (HSPC) GT composed of CD34+ HSPCs transduced ex vivo with a self-inactivating lentiviral vector encoding human WAS cDNA under endogenous promoter control.
Results
At data cut, 23 patients have been treated with OTL-103, as part of phase I/II (n=8) or III (n=6) clinical trials or Expanded Access Program (EAP) (n=9), with median follow-up of 3.6 years (range: 0.4-10.5). All received rituximab and reduced-intensity conditioning pre-GT. Median age at treatment was 3.1 years (range: 1.0-35.1). Seventeen patients received fresh OTL-103, while six received cryopreserved formulation. All were alive, except one EAP subject who died early post-GT due to deterioration of a pre-existing neurological condition. To date, no GT-related adverse events or signs of insertional mutagenesis have been reported. Integrated efficacy analysis performed in trials’ subjects showed sustained engraftment of gene-corrected cells, leading to marked increase of WASP expression in platelets and lymphocytes. This resulted in improved platelet count and T-cell functionality, with substantial reduction of moderate/severe bleedings and severe infections. Bleeding and antimicrobial prophylaxis was stopped. Eczema improved and clinical autoimmunity resolved.
Conclusions
Our data show that lentiviral GT for WAS is well tolerated and leads to sustained clinical benefit, highlighting its potential as an alternative treatment for WAS patients.
INNOVATIVE PRE-TRANSPLANT CONDITIONINGS FOR IMMUNE DYSREGULATION DISORDERS
Abstract
Background and Aims
Hematopoietic stem cell transplantation (HSCT) is the only cure for severe immune dysregulation. Conditioning regimens are crucial for successful HSCT to eliminate resident hematopoietic stem/progenitor cells (HSPCs), but current chemo/radiotherapy conditionings may induce severe toxicities. We demonstrated the efficacy of non-genotoxic conditioning with anti-CD45 mAb conjugated with saporin (CD45-SAP) in Recombination Activating gene (Rag1)-deficient mouse models. To maximize the therapeutical potential of CD45-SAP, we are optimizing a protocol based on CD45-SAP combined with a low dose of clinically relevant chemotherapies, treosulfan and fludarabine (Treo/Flu), in distinct preclinical models.
Methods
We tested the depletion activity of a full dose of Treo/Flu (7g/1g /Kg) in Rag1-knock-out (KO), Rag1-F971L and Wiskott-Aldrich Syndrome gene (Was)-KO mice, showing a spectrum of immunodeficiency and autoimmunity. We assessed, in Rag1-KO mice, the engraftment and immune reconstitution achieved by lower doses of Treo/Flu with or without CD45-SAP (3mg/kg). Transgenic mice were transplanted with wild-type (WT) Lineage negative cells (Lin-). Depletion activity, engraftment and immunological reconstitution were assessed by flow cytometry, histology, and ELISA.
Results
Full Treo/Flu dose efficiently depletes HSPCs and lymphoid progenitors in all mouse models resulting in high myeloid chimerism and immune cell reconstitution in Rag1-KO mice transplanted with WT Lin- cells. The combination of CD45-SAP with low doses of Treo/Flu showed a dose dependent synergistic effect increasing both myeloid chimerism and immune recovery, as compared to CD45-SAP alone.
Conclusions
Preliminary data show that CD45-SAP combined with low doses of Treo/Flu allows robust immune reconstitution in Rag1-KO mice, paving the way for further studies in the other immune disorders.
LATE-ONSET ENTERIC VIRUS INFECTION ASSOCIATED WITH HEPATITIS (EVAH) IN TRANSPLANTED SCID PATIENTS
Abstract
Background and Aims
Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments of severe combined immunodeficiency (SCID). Nevertheless, late-onset manifestations are not uncommon including hepatitis.
Methods
SCID patients with late-onset hepatitis post HSCT or GT were investigated using multi-omics, pathology and metagenomics.
Results
Eleven patients developed persistent hepatitis at a median time of 6 years for SCID related to IL2RG (n=10) or DCLRE1C (n=1) deficiency (SCIDH+). Clinical consequences of this condition can be severe, up to death (n=3). It was associated with the detection of enteric viruses (Aichi virus, Norovirus and Sapovirus) in liver and/or stools, which were not found in stools of healthy asymptomatic similarly transplanted patients (n=12, SCIDH-). Mass-cytometry analysis on peripheral blood mononuclear cells of 6 SCIDH+ compared to 7 SCIDH- identified an expansion of CD38high HLA-DRhigh CD127low CD8+ T cells. Type I and II IFN signatures identified by scRNAseq were mostly but not exclusively found in CD8+ T cells. Among a cohort of 114 long-term survivors post HSCT or GT for SCID, hepatitis was strongly associated with absence of myeloablation, split chimerism and defective B cell function.
Conclusions
Overall, this condition characterized by enteric virus infection associated with hepatitis (named EVAH) represents 25% of SCID patients who did not receive myeloablation and were on immunoglobulin replacement. Partially myeloablative re-transplantation or GT could reconstitute T and B cell immunity and lead to remission of hepatitis, concomitantly to viral clearance, as observed in 5 patients. Beyond SCID, a same dysimmune process could occur in inherited or acquired B-cell defects.