慢病毒基因治疗联合小剂量白消安治疗 X-连锁重症联合免疫缺陷病 1 型婴儿
Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1.
机构信息
From the Departments of Bone Marrow Transplantation and Cellular Therapy (E.M., B.T., W.J., S.G.), Hematology (S.Z., Z.M., J.C., J.D., X.T., B.Y.R., M.J.W., B.P.S.), Therapeutics Production and Quality (T.L., M.M.M.), Immunology (H.A., B.Y.), Pharmaceutical Sciences (S.J.C.), Biostatistics (G.K., C.L.), and Infectious Diseases (G.M.), St. Jude Children's Research Hospital, Memphis, TN; the Allergy and Clinical Immunology Division, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru (J.C.A.B.); the Department of Pediatrics, Allergy-Immunology Division, Children's Hospital Los Angeles, Los Angeles (J.A.C.), and the Department of Pediatrics, Division of Pediatric Allergy-Immunology-Bone Marrow Transplantation, University of California, San Francisco (UCSF) Benioff Children's Hospital, San Francisco (J.R.L.-B., J.M.P., M.J.C.) - both in California; the Department of Pediatrics, Pediatric Allergy and Immunology, University of New Mexico, Albuquerque (E.D.); University of Oklahoma Health Sciences Center, Tulsa (J.T.L.); Departamento de Pediatria da Universidade de Taubaté, Conselho Nacional de Medicina, São Paulo (A.C.M.A.); Copperfield Childcare, Claremont, South Africa (H.W.); and the Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (S.S.D.R., H.L.M.).
出版信息
N Engl J Med. 2019 Apr 18;380(16):1525-1534. doi: 10.1056/NEJMoa1815408.
BACKGROUND
Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.
METHODS
We performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.
RESULTS
Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.
CONCLUSIONS
Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).
背景
当无法获得匹配的同胞供体时，异基因造血干细胞移植治疗 X 连锁严重联合免疫缺陷（SCID-X1）往往无法重建与 T 细胞、B 细胞和自然杀伤（NK）细胞相关的免疫，除非给予大剂量化疗。在以前的研究中，自体基因治疗用 γ-逆转录病毒载体未能重建 B 细胞和 NK 细胞免疫，并因载体相关白血病而变得复杂。
方法
我们在 8 名新诊断为 SCID-X1 的婴儿中进行了一项双中心、1-2 期安全性和疗效研究，即在低暴露、靶向性白消安预处理后，将互补 DNA 通过慢病毒载体转移到骨髓干细胞中。
结果
8 名 SCID-X1 婴儿中位随访 16.4 个月。骨髓采集、白消安预处理和细胞输注均无意外副作用。在 7 名婴儿中，输注后 3 至 4 个月 CD3+、CD4+和幼稚 CD4+T 细胞和 NK 细胞数量恢复正常，并伴有 T 细胞、B 细胞、NK 细胞、髓样细胞和骨髓祖细胞中的载体标记。第 8 名婴儿最初 T 细胞计数不足，但在未接受白消安预处理的情况下，该婴儿接受了基因校正细胞的增强后，T 细胞得到了发展。所有婴儿以前的感染均已清除，所有婴儿均继续正常生长。8 名婴儿中的 7 名 IgM 水平恢复正常，其中 4 名停止了静脉注射免疫球蛋白补充；这 4 名中有 3 名对疫苗有反应。对 7 名婴儿进行了载体插入位点分析，结果显示所有 7 名婴儿均为多克隆模式，无克隆优势。
结论
在新诊断为 SCID-X1 的婴儿中，将慢病毒载体基因治疗与低暴露、靶向性白消安预处理相结合，具有低级别急性毒性作用，并导致转导细胞的多谱系植入、功能性 T 细胞和 B 细胞的重建以及 NK 细胞计数的正常化，中位随访 16 个月。（由美国黎巴嫩叙利亚联合慈善协会等资助；LVXSCID-ND ClinicalTrials.gov 编号，NCT01512888）。
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