Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome
A Magnani, M Semeraro, F Adam, C Booth, L Dupré, E C Morris, A Gabrion, C Roudaut, D Borgel, A Toubert, E Clave, C Abdo, G Gorochov, R Petermann, M Guiot, M Miyara, D Moshous, E Magrin, A Denis, F Suarez, C Lagresle, A M Roche, J Everett, A Trinquand, M Guisset, J Xu Bayford, S Hacein-Bey-Abina, A Kauskot, R Elfeky, C Rivat, S Abbas, H B Gaspar, E Macintyre, C Picard, F D Bushman, A Galy, A Fischer, E Six, A J Thrasher, M Cavazzana, A Magnani, M Semeraro, F Adam, C Booth, L Dupré, E C Morris, A Gabrion, C Roudaut, D Borgel, A Toubert, E Clave, C Abdo, G Gorochov, R Petermann, M Guiot, M Miyara, D Moshous, E Magrin, A Denis, F Suarez, C Lagresle, A M Roche, J Everett, A Trinquand, M Guisset, J Xu Bayford, S Hacein-Bey-Abina, A Kauskot, R Elfeky, C Rivat, S Abbas, H B Gaspar, E Macintyre, C Picard, F D Bushman, A Galy, A Fischer, E Six, A J Thrasher, M Cavazzana
Abstract
Patients with Wiskott-Aldrich syndrome (WAS) lacking a human leukocyte antigen-matched donor may benefit from gene therapy through the provision of gene-corrected, autologous hematopoietic stem/progenitor cells. Here, we present comprehensive, long-term follow-up results (median follow-up, 7.6 years) (phase I/II trial no. NCT02333760 ) for eight patients with WAS having undergone phase I/II lentiviral vector-based gene therapy trials (nos. NCT01347346 and NCT01347242 ), with a focus on thrombocytopenia and autoimmunity. Primary outcomes of the long-term study were to establish clinical and biological safety, efficacy and tolerability by evaluating the incidence and type of serious adverse events and clinical status and biological parameters including lentiviral genomic integration sites in different cell subpopulations from 3 years to 15 years after gene therapy. Secondary outcomes included monitoring the need for additional treatment and T cell repertoire diversity. An interim analysis shows that the study meets the primary outcome criteria tested given that the gene-corrected cells engrafted stably, and no serious treatment-associated adverse events occurred. Overall, severe infections and eczema resolved. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. The results suggest that lentiviral gene therapy provides sustained clinical benefits for patients with WAS.
Conflict of interest statement
A.J.T. holds equity in Orchard Therapeutics. A. Galy and S.A. work at Genethon (sponsor). All other authors declare no competing interests.
© 2022. The Author(s).
Figures
References
- Thrasher AJ, Burns SO. WASP: a key immunological multitasker. Nat. Rev. Immunol. 2010;10:182–192. doi: 10.1038/nri2724.
- Candotti F. Clinical manifestations and pathophysiological mechanisms of the Wiskott-Aldrich syndrome. J. Clin. Immunol. 2018;38:13–27. doi: 10.1007/s10875-017-0453-z.
- Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr. Opin. Hematol. 2011;18:42–48. doi: 10.1097/MOH.0b013e32834114bc.
- Zhu Q, et al. The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene. Blood. 1995;86:3797–3804. doi: 10.1182/blood.V86.10.3797.bloodjournal86103797.
- Imai K, et al. Clinical course of patients with WASP gene mutations. Blood. 2004;103:456–464. doi: 10.1182/blood-2003-05-1480.
- Mahlaoui N, et al. Characteristics and outcome of early-onset, severe forms of Wiskott-Aldrich syndrome. Blood. 2013;121:1510–1516. doi: 10.1182/blood-2012-08-448118.
- Dupuis-Girod S, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111:622–627. doi: 10.1542/peds.111.5.e622.
- Ozsahin H, et al. Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation. Blood. 2008;111:439–445. doi: 10.1182/blood-2007-03-076679.
- Moratto D, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. 2011;118:1675–1684. doi: 10.1182/blood-2010-11-319376.
- Shin CR, et al. Outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome. Bone Marrow Transplant. 2012;47:1428–1435. doi: 10.1038/bmt.2012.31.
- Elfeky RA, et al. One hundred percent survival after transplantation of 34 patients with Wiskott-Aldrich syndrome over 20 years. J. Allergy Clin. Immunol. 2018;142:1654–1656. doi: 10.1016/j.jaci.2018.06.042.
- Burroughs LM, et al. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report. Blood. 2020;135:2094–2105. doi: 10.1182/blood.2019002939.
- Balashov, D. et al. A conditioning regimen with plerixafor is safe and improves the outcome of TCRαβ+ and CD19+ cell-depleted stem cell transplantation in patients with Wiskott-Aldrich syndrome. Biol. Blood Marrow Transplant.24, 1432–1440 (2018).
- Wada T, et al. Second-site mutation in the Wiskott-Aldrich syndrome (WAS) protein gene causes somatic mosaicism in two WAS siblings. J. Clin. Invest. 2003;111:1389–1397. doi: 10.1172/JCI15485.
- Davis BR, et al. Somatic mosaicism in the Wiskott-Aldrich syndrome: molecular and functional characterization of genotypic revertants. Clin. Immunol. 2010;135:72–83. doi: 10.1016/j.clim.2009.12.011.
- Trifari S, et al. Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: analysis of function and distribution in lymphoid organs. J. Allergy Clin. Immunol. 2010;125:439–448. doi: 10.1016/j.jaci.2009.11.034.
- Braun CJ, et al. Gene therapy for Wiskott-Aldrich syndrome: long-term efficacy and genotoxicity. Sci. Transl. Med. 2014;6:227ra33. doi: 10.1126/scitranslmed.3007280.
- Cavazzana M, Bushman FD, Miccio A, André-Schmutz I, Six E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug Discov. 2019;18:447–462. doi: 10.1038/s41573-019-0020-9.
- Aiuti A, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341:1233151. doi: 10.1126/science.1233151.
- Hacein-Bey Abina S, et al. Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. JAMA. 2015;313:1550–1563. doi: 10.1001/jama.2015.3253.
- Ferrua F, et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 2019;6:239–253. doi: 10.1016/S2352-3026(19)30021-3.
- Morris EC, et al. Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult. Blood. 2017;130:1327–1335. doi: 10.1182/blood-2017-04-777136.
- Dupré L, et al. Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction. Mol. Ther. 2004;10:903–915. doi: 10.1016/j.ymthe.2004.08.008.
- Stalder JF, et al. Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186:23–31. doi: 10.1159/000247298.
- Pielou EC. The measurement of diversity in different types of biological collections. J. Theor. Biol. 1966;13:131–144. doi: 10.1016/0022-5193(66)90013-0.
- Ramezani H. A note on the normalized definition of Shannon’s diversity index in landscape pattern analysis. Environ. Nat. Resources Res. 2012;2:54–60.
- Rivers E, Worth A, Thrasher AJ, Burns SO. Bleeding and splenectomy in Wiskott-Aldrich syndrome: a single-centre experience. J. Allergy Clin. Immunol. Pract. 2019;7:1042–1044. doi: 10.1016/j.jaip.2018.07.009.
- Pala F, et al. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J. Clin. Invest. 2015;125:3941–3951. doi: 10.1172/JCI82249.
- Castiello MC, et al. B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome. J. Allergy Clin. Immunol. 2015;136:692–702. doi: 10.1016/j.jaci.2015.01.035.
- Rengan R, et al. Actin cytoskeletal function is spared, but apoptosis is increased, in WAS patient hematopoietic cells. Blood. 2000;95:1283–1292. doi: 10.1182/blood.V95.4.1283.004k44_1283_1292.
- Westerberg LS, et al. WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function. Blood. 2008;112:4139–4147. doi: 10.1182/blood-2008-02-140715.
- Sabri S, et al. Deficiency in the Wiskott-Aldrich protein induces premature proplatelet formation and platelet production in the bone marrow compartment. Blood. 2006;108:134–140. doi: 10.1182/blood-2005-03-1219.
- Sereni L, et al. Autonomous role of Wiskott-Aldrich syndrome platelet deficiency in inducing autoimmunity and inflammation. J. Allergy Clin. Immunol. 2018;142:1272–1284. doi: 10.1016/j.jaci.2017.12.1000.
- Sereni L, et al. Lentiviral gene therapy corrects platelet phenotype and function in patients with Wiskott-Aldrich syndrome. J. Allergy Clin. Immunol. 2019;144:825–838. doi: 10.1016/j.jaci.2019.03.012.
- Charrier S, et al. Wiskott-Aldrich syndrome protein-deficient hematopoietic cells can be efficiently mobilized by granulocyte colony-stimulating factor. Haematologica. 2013;98:1300–1308. doi: 10.3324/haematol.2012.077040.
- Muñoz, P. et al. WAS promoter-driven lentiviral vectors mimic closely the lopsided WASP expression during megakaryocytic differentiation. Mol. Ther. Methods Clin. Dev.19, 220–235 (2020).
- Astrakhan A, et al. Ubiquitous high-level gene expression in hematopoietic lineages provides effective lentiviral gene therapy of murine Wiskott-Aldrich syndrome. Blood. 2012;119:4395–4407. doi: 10.1182/blood-2011-03-340711.
- Singh S, et al. Safe and effective gene therapy for murine Wiskott-Aldrich syndrome using an insulated lentiviral vector. Mol. Ther. Methods Clin. Dev. 2016;4:1–16. doi: 10.1016/j.omtm.2016.11.001.
- Dupré, L. et al. Wiskott-Aldrich syndrome protein regulates lipid raft dynamics during immunological synapse formation. Immunity17, 157–166 (2002).
- Schatorjé EJH, et al. Paediatric reference values for the peripheral T cell compartment. Scand. J. Immunol. 2012;75:436–444. doi: 10.1111/j.1365-3083.2012.02671.x.
- Segel G, Halterman J. Neutropenia in pediatric practice. Pediatr. Rev. 2008;29:12–23. doi: 10.1542/pir.29-1-12.
- Picard C. Comment explorer un déficit immunitaire héréditaire? Rev. Prat. 2007;57:1671–1676.
- Arruda LCM, et al. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients. Blood Adv. 2018;2:126–141. doi: 10.1182/bloodadvances.2017011072.
- Brüggemann M, et al. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study. Leukemia. 2019;33:2241–2253. doi: 10.1038/s41375-019-0496-7.
- Houmadi R, et al. The Wiskott-Aldrich syndrome protein contributes to the assembly of the LFA-1 nanocluster belt at the lytic synapse. Cell Rep. 2018;22:979–991. doi: 10.1016/j.celrep.2017.12.088.
- Adam F, Verbeuren TJ, Fauchère JL, Guillin MC, Jandrot-Perrus M. Thrombin-induced platelet PAR4 activation: role of glycoprotein ibandadp. J. Thromb. Haemost. 2003;1:798–804. doi: 10.1046/j.1538-7836.2003.00138.x.
- Adam F, et al. Platelet JNK1 is involved in secretion and thrombus formation. Blood. 2010;115:4083–4092. doi: 10.1182/blood-2009-07-233932.
- Berrou E, et al. A mutation of the human EPHB2 gene leads to a major platelet functional defect. Blood. 2018;132:2067–2077. doi: 10.1182/blood-2018-04-845644.
- Kiefel V, Santoso S, Weisheit M, Mueller-Eckhardt C. Monoclonal antibody-specific immobilization of platelet antigens (MAIPA): a new tool for the identification of platelet-reactive antibodies. Blood. 1987;70:1722–1726. doi: 10.1182/blood.V70.6.1722.1722.
- Sherman E, et al. INSPIIRED: a pipeline for quantitative analysis of sites of new DNA integration in cellular genomes. Mol. Ther. Methods Clin. Dev. 2017;4:39–49. doi: 10.1016/j.omtm.2016.11.002.
- Berry CC, et al. INSPIIRED: quantification and visualization tools for analyzing integration site distributions. Mol. Ther. Methods Clin. Dev. 2017;4:17––26. doi: 10.1016/j.omtm.2016.11.003.
- Six E, et al. Clonal tracking in gene therapy patients reveals a diversity of human hematopoietic differentiation programs. Blood. 2020;135:1219––1231. doi: 10.1182/blood.2019002350.
Source: PubMed