Combining Mobilizing Agents with Busulfan to Reduce Chemotherapy-Based Conditioning for Hematopoietic Stem Cell Transplantation

Abstract

In the context of hematopoietic stem cell (HSC) transplantation, conditioning with myelo- and immune-ablative agents is used to eradicate the patient’s diseased cells, generate space in the marrow and suppress immune reactions prior to the infusion of donor HSCs. While conditioning is required for effective and long-lasting HSC engraftment, currently used regimens are also associated with short and long-term side effects on extramedullary tissues and even mortality. Particularly in patients with severe combined immunodeficiency (SCID), who are generally less than 1-year old at the time of transplantation and often suffer from existing comorbidities. There is a pressing need for development of alternative, less toxic conditioning regimens. Hence, we here aimed to improve efficacy of currently used myeloablative protocols by combining busulfan with stem-cell niche-directed therapeutic agents (G-CSF or plerixafor) that are approved for clinical use in stem cell mobilization. T, B and myeloid cell recovery was analyzed in humanized NSG mice after different conditioning regimens. Increasing levels of human leukocyte chimerism were observed in a busulfan dose-dependent manner, showing comparable immune recovery as with total body irradiation in CD34-transplanted NSG mice. Notably, a better T cell reconstitution compared to TBI was observed after busulfan conditioning not only in NSG mice but also in SCID mouse models. Direct effects of reducing the stem cell compartment in the bone marrow were observed after G-CSF and plerixafor administration, as well as in combination with low doses of busulfan. Unfortunately, these direct effects on the stem population in the bone marrow were not reflected in increased human chimerism or immune recovery after CD34 transplantation in NSG mice. These results indicate moderate potential of reduced conditioning regimens for clinical use relevant for all allogeneic transplants.

IGF2-tagging of GAA promotes full correction of murine Pompe disease at a clinically relevant dosage of lentiviral gene therapy

“…Busulfan- or treosulfan-based regimens have been shown to be immunosuppressive and myeloablative, and have a similar ablative nature compared with the non-clinically relevant irradiation. 101 Future experiments with clinically relevant preconditioning regimens are therefore required to confirm the bona fide translation of our approach to clinical settings. Our results demonstrate that correction of Pompe disease pathology correlates with the strength of the preconditioning administrated prior to transplantation to maximize chimerism and thereby expression of the GAAco and IGF2.GAAco transgenes.…”

Lentiviral gene therapy prevents anti-human acid α-glucosidase antibody formation in murine Pompe disease

“…These are immunosuppressive and myeloablative regimens that have a similar ablative nature compared with irradiation. 77 Extensive experience in the clinic over the years as well as therapeutic drug monitoring resulted in improved outcome of these regimens and are at this moment the most commonly used agents in the clinic for current gene therapy trials in patients with inborn errors. 75,[78][79][80] Recent reports suggest that the recommended ERT dose currently used for classic infantile patients (20 mg/kg biweekly) is insufficient to correct disease symptoms and that increasing the dose to weekly infusions of 40 mg/kg provides a better prognosis.…”

Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities

“…Several studies show that compared with myeloablative stem cell transplantation, reduced-intensity conditioning stem cell transplantation reduces thymus damage and promotes immune reconstitution. However, some studies show no significant difference in recipient immune reconstitution between these two transplantation methods[ 60 , 96 - 98 ].…”