Cryopreserved Ex Vivo-Expanded Allogeneic Myeloid Progenitor Cell Product Protects Neutropenic Mice from a Lethal Fungal Infection

Abstract

Severe neutropenia induced by chemotherapy or conditioning for hematopoietic cell transplantation often results in morbidity and mortality due to infection by opportunistic pathogens. A system has been developed to generate ex vivo-expanded mouse myeloid progenitor cells (mMPCs) that produce functional neutrophils in vivo upon transplantation in a pathogen challenge model. It has previously been demonstrated that transplantation of large numbers of freshly isolated myeloid progenitors from a single donor provides survival benefit in radiation-induced neutropenic mice. In the present work, an ex vivo-expanded and cryopreserved mMPC product generated from an allogeneic donor pool retains protective activity in vivo in a lethal fungal infection model. Infusion of the allogeneic pooled mMPC product is effective in preventing death from invasive Aspergillus fumigatus in neutropenic animals, and protection is dose dependent. Cell progeny from the mMPC product is detected in the bone marrow, spleen, blood, and liver by flow cytometry 1 week postinfusion but is no longer evident in most animals 4 weeks posttransplant. In this model, the ex vivo-generated pooled allogeneic mMPC product (i) expands and differentiates in vivo; (ii) is functional and prevents death from invasive fungal infection; and (iii) does not permanently engraft or cause allosensitization. These data suggest that an analogous ex vivo-expanded human myeloid progenitor cell product may be an effective off-the-shelf bridging therapy for the infectious complications that develop during hematopoietic recovery following hematopoietic cell transplantation or intensive chemotherapy.

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

“…Sargramostim’s actions on alveolar macrophages, dendritic cells, and T cells may allow for complementary immune response changes versus increases in cell numbers as seen with other agents such as rhu G-CSF ( Figure 1 ) ( 5 , 11 , 12 , 161 , 162 ). Other novel products, such as hematopoietc stem cell-derived ex vivo -expanded myeloid progenitor cells and phenotypically typed functional granulocytes, have been shown to be efficacious in animal models ( 184 , 185 ).…”

Assessment of safety and immunogenicity of MHC homozygous iPSC-derived CD34+ hematopoietic progenitors in an NHP model

“…7 To overcome these limitations, administration of ex vivo expanded myeloid progenitors has been explored as a way to facilitate a more rapid myeloid recovery and improve overall survival after myeloablation. [8][9][10][11][12][13][14][15] Myeloid progenitors produced ex vivo from somatic hematopoietic stem/progenitor cells (HSPCs) have been shown to reduce BM aplasia and fungal and bacterial infections and improve overall survival after BM ablation in animal models. [8][9][10][11][12]15 Recent studies have also demonstrated that HSPCs improve survival from sepsis in a mouse model.…”

“…[8][9][10][11][12][13][14][15] Myeloid progenitors produced ex vivo from somatic hematopoietic stem/progenitor cells (HSPCs) have been shown to reduce BM aplasia and fungal and bacterial infections and improve overall survival after BM ablation in animal models. [8][9][10][11][12]15 Recent studies have also demonstrated that HSPCs improve survival from sepsis in a mouse model. 16 The benefits of a progenitor-based strategy are supported by clinical trials demonstrating the safety and feasibility of using non-HLA-matched ex vivo expanded cord blood progenitors as an alternative to granulocyte transfusion in patients with acute myeloid and other leukemias after intensive chemotherapy.…”