Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning

• Published in: Journal of clinical immunology 2015-05, Vol.35 (4), p.384-398
• Main Authors: Otsu, Makoto, Yamada, Masafumi, Nakajima, Satoru, Kida, Miyuki, Maeyama, Yoshihiro, Hatano, Norikazu, Toita, Nariaki, Takezaki, Shunichiro, Okura, Yuka, Kobayashi, Ryoji, Matsumoto, Yoshinori, Tatsuzawa, Osamu, Tsuchida, Fumiko, Kato, Shunichi, Kitagawa, Masanari, Mineno, Junichi, Hershfield, Michael S., Bali, Pawan, Candotti, Fabio, Onodera, Masafumi, Kawamura, Nobuaki, Sakiyama, Yukio, Ariga, Tadashi
• Format: Article
• Language: English
• Subjects: Adenosine Deaminase - deficiency; Adenosine Deaminase - genetics; Adenosine Deaminase - immunology; Adenosine Deaminase - therapeutic use; Adolescent; Agammaglobulinemia - diagnosis; Agammaglobulinemia - genetics; Agammaglobulinemia - immunology; Agammaglobulinemia - therapy; Age of Onset; Biomedical and Life Sciences; Biomedicine; Cell Differentiation; Child, Preschool; Enzyme Activation; Enzyme Replacement Therapy; Gammaretrovirus - genetics; Gene Expression; Genetic Therapy; Genetic Vectors - genetics; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Immunity; Immunology; Immunophenotyping; Infant; Infant, Newborn; Infectious Diseases; Internal Medicine; Japan; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Medical Microbiology; Mutation; Original Research; Severe Combined Immunodeficiency - diagnosis; Severe Combined Immunodeficiency - genetics; Severe Combined Immunodeficiency - immunology; Severe Combined Immunodeficiency - therapy; Transduction, Genetic; Transgenes; Treatment Outcome
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-015-0157-1

Objective We here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency. Patients and Methods Pt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34 + cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the γ-retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed. Results Treatment was well tolerated, and no serious adverse events were observed. Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in pts 1 and 2, peaked at 408/mm 3 and 1248/mm 3 , approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential. Conclusions Outcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.