Transfusable neutrophil progenitors as cellular therapy for the prevention of invasive fungal infections

Abstract

The use of mature neutrophil (granulocyte) transfusions for the treatment of neutropenic patients with invasive fungal infections (IFIs) has been the focus of multiple clinical trials. Despite these efforts, the transfusion of mature neutrophils has resulted in limited clinical benefit, likely owing to problems of insufficient numbers and the very short lifespan of these donor cells. In this report, we employed a system of conditionally immortalized murine neutrophil progenitors that are capable of continuous expansion, allowing for the generation of unlimited numbers of homogenous granulocytemacrophage progenitors (GMPs). These GMPs were assayed in vivo to demonstrate their effect on survival in 2 models of IFI: candidemia and pulmonary aspergillosis.Mature neutrophils derived from GMPs executed all cardinal functions of neutrophils.Transfused GMPs homed to the bone marrow and spleen, where they completed normal differentiation to mature neutrophils. These neutrophils were capable of homing and extravasation in response to inflammatory stimuli using a sterile peritoneal challenge model. Furthermore, conditionally immortalized GMP transfusions significantly improved survival in models of candidemia and pulmonary aspergillosis. These data confirm the therapeutic benefit of prophylactic GMP transfusions in the setting of neutropenia and encourage development of progenitor cellular therapies for the management of fungal disease in high-risk patients.

How are granulocytes for transfusion best used? The past, the present and the future

“…48 Three studies to date have used conditionally immortalised myeloid progenitor cells for the treatment of sepsis. Sykes et al 49 used a murine model of fungal infection showing increased survival of infected mice. One recent clinical study used CD34 + stem cells manipulated into a myeloid progenitor state in a randomised phase II study, administered as prophylaxis during induction therapy in patients with AML.…”

“…Inhibition of anti-apoptotic pathways to produce a longerlived cellular product or development of an immortalised progenitor capable of ongoing maturation. 49 2. Enhancement or alteration of neutrophil migration and maturation: Toll-like receptors crucial for pathogen recognition are downregulated during prolonged activation in sepsis leading to decreased neutrophil activation.…”

“…Three studies to date have used conditionally immortalised myeloid progenitor cells for the treatment of sepsis. Sykes et al 49 . used a murine model of fungal infection showing increased survival of infected mice.…”

“…Possible targets from the literature for manipulation of stem cell‐derived neutrophil cellular products for treatment of infection include those illustrated in Figure 1, as summarised below: Inhibition of anti‐apoptotic pathways to produce a longer‐lived cellular product or development of an immortalised progenitor capable of ongoing maturation 49 Enhancement or alteration of neutrophil migration and maturation: Toll‐like receptors crucial for pathogen recognition are downregulated during prolonged activation in sepsis leading to decreased neutrophil activation 56 .…”

Lung and gut microbiomes in pulmonary aspergillosis: Exploring adjunctive therapies to combat the disease

“…Among the adaptive immune responses, from a neutropenia perspective, transfusable neutrophil progenitors serve as new cellular therapies for the prevention of IPA. This treatment produces unlimited numbers of homogenous granulocytemacrophage progenitors, greatly improving survival in models of PA (63). Although an increasing number of new therapeutic strategies are being discovered, most of the studies are still limited to animal experiments.…”