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Hematopoietic stem cell (HSC) gene therapy is a demonstrated effective treatment for X-linked severe combined immunodeficiency (SCID-X1), but B-cell reconstitution and function has been deficient in many of the gene therapy treated patients. Cytoreductive preconditioning is known to improve HSC engraftment, but in general it is not considered for SCID-X1 since the poor health of most of these patients at diagnosis and the risk of toxicity preclude the conditioning used in standard bone marrow stem cell transplantation. We hypothesized that mobilization of HSC by granulocyte colony-stimulating factor (G-CSF) should create temporary space in bone marrow niches to improve engraftment and thereby B-cell reconstitution. In the present pilot study supplementing our earlier preclinical evaluation (Huston et al., 2011), Il2rg-/ -mice pretreated with G-CSF were transplanted with wild-type lineage negative (Lin -) cells or Il2rg -/ -Lin -cells transduced with therapeutic IL2RG lentiviral vectors. Mice were monitored for reconstitution of lymphocyte populations, level of donor cell chimerism, and antibody responses as compared to 2 Gy total body irradiation (TBI), previously found effective in promoting B-cell reconstitution. The results demonstrate that G-CSF promotes B-cell reconstitution similar to low-dose TBI and provides proof of principle for an alternative approach to improve efficacy of gene therapy in SCID patients without adverse effects associated with cytoreductive conditioning.

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confirmed by BLI. Interestingly, the IFNa-GT group showed an increased content of human CD33+ HLA-DR+ CD11c+ dendritic cells (including a pro-inflammatory SLAN+ subset) and increased levels of CD16 and HLA-DR expression on human myeloid cells within the myeloma-bearing BM, suggestive of myeloid cell reprogramming towards a more immune-stimulatory state. Moreover, IFNa-GT induced an upregulation of CD38 expression (on average 1.4 fold on myeloma cells). This provides a rationale for combining IFNa-GT with other anti-MM drugs. Indeed, the anti-MM effect of Daratumumab, Lenalidomide or Carfilzomib was enhanced by IFNa-GT, without excessive toxicity on the HSPC graft. Summary/Conclusion: Our studies conducted both in the immunocompetent Vk*Myc murine model as well as in the hematochimeric xenotransplantation setting demonstrate that IFNa-GT has robust anti-MM effect and may subvert the immunosuppressive MM TME, acting both on myeloma cells as well as on the immune infiltrate. A phase I/II dose-escalation study of IFNa-GT in patients with early-relapsed multiple myeloma has recently been approved and is starting accrual in March 2019.