Table 3.
The development of approaches for iMph-based cell therapy
| Disease/ application |
Reference | iPSC/iMph source | iPSC/iMph genetic modification (other manipulations) |
Model | Main results |
|---|---|---|---|---|---|
| PAP | Lachmann et al. [115] |
PAP patient (mutation in CSF2RA exon7) |
Lentiviral transduction of CSF2RA transgene to PAP-iPSCs | In vitro analysis of PAP-iMphs and genetically corrected PAP-iMphs |
PAP-iMphs: a reduced response to GM-CSF: an impaired CD11b upregulation, a decreased GM-CSF uptake, a hampared phagocytosis, a reduced STAT5-phosphorylation Corrected PAP-iMphs: correction of iMph response to GM-CSF |
| Kuhn et al. [116] |
PAP patient (mutation in CSF2RA exon7) |
TALEN-mediated integration of CSF2RA into PAP-iPSCs; | In vitro analysis of PAP-iMphs and genetically corrected PAP-iMphs | Corrected iMphs: a restoration of cell response to GM-CSF: restored STAT5 phosphorylation and GM-CSF uptake | |
| Mucci et al. [117] |
BL/6 (CD45.1) WT mice |
- | intratracheal transplantation of WT iMphs into Csf2rb−/− BL/6 (CD45.2) recipients |
iMph therapeutic efficacy: a reduced opacity and protein levels in the BALF of recipient mice, an improved CT and lung tissue histology iMph biodistribution /persistence: iMph accumulate in alveolar spaces; iMph can be detected for up to 6 months |
|
| Happle et al. [156] | Healthy donor | - | Weekly intratracheal transplantations of iMphs into humanized PAP mice (4 weeks) |
iMph therapeutic efficacy: a reduced BALF protein level, a reduced level of surfactant D iMph biodistribution/safety: iMphs are found in the lungs near large airways, but not in other tissues (except human RNA been detected in the spleens of recipient mice); no signs of teratoma or tumors were recorded |
|
| ADA deficiency | Litvack et al. [114] | Mouse ESCs |
- (iMph conditioning with GM-CSF and other factors to generate AL-iMphs) |
Repeated intranasal administration to untreated ADA−/− mouse pups; Single i.t. administration to 4 week-old ADA−/− mice (previously treated with PEG-ADA) |
iMph therapeutic efficacy: an increased mice survival in the absence of the other therapy; blood oxygen saturation was recovered; mucous substance in the alveoli was reduced; signs of pulmonary epithelial repair were detected |
| Infectious diseases | Ackermann et al. [46] | Healthy donor | - | In vivo: i.t. transfer into immunodeficient humanized mice infected with P. aeruginosa simultaneously with or 4 h prior to iMph transfer | iMph therapeutic efficacy: a reduction of infection scores, including a reduction of hemmorage, granulocytic infiltration of the lung tissue, edema and weight loss |
| Taylor et al. [96] | Healthy donor | USP18 knock-out using CRISPR/Cas9 | In vitro infection with HIV-1 | In vitro effects: a reduced HIV-1 replication in engineered iMphs | |
| Cancer | Senju et al. [23] | Healthy donor | iPSC electroporation with scFv specific to amyloid-β or CD20 |
In vitro: phagocytosis of amyloid-β-coated microbeads; engulfment and digestion of BALL-1 tumor cells; In vivo: simultaneous transfer of aCD20-iMphs and BALL-1 to SCID mice |
Anti-amyloid-β-iMphs: an enhanced phagocytosis of amyloid-β coated microbeads; Anti-CD20-iMphs: the digestion of BALL-1 cell line in vitro; the inhibition of tumor growth in vivo |
|
Koba et al. [130] Senju et al. [131] |
Healthy donor |
iPSC electroporation with scFv specific to HER2/neu linked to FcgRI; lentiviral transduction of iPS-ML with IFN-α, IFN-β, IFN-γ, TNF-α, FAS-ligand, or TRAIL |
In vitro: co-culture with human gastric (NUGC-4) and pancreatic (MIAPaCa-2) cancer cell lines In vivo: the transfer of PKH26-labeled iPS-MLs to SCID mice 15 days after the transfer of NUGC-4 or MIAPaCa-2 cell lines |
In vitro effects: the inhibition of tumor growth (most efficient for HER2/neu-iMphs) Therapeutic efficacy: no anti-cancer activity of HER2/neu-iMphs; inhibition of tumor growth by iPS-ML/IFN-β and iPS-ML/anti-HER2/IFN-β |
|
| Miyashita et al. [132] | Healthy donor |
Lentiviral transduction of iPS-ML with IFN-α or IFN-β |
In vitro: inhibition of human malignant melanoma cell line SK-MEL28 growth In vivo: intreperitoneal transfers of PKH26-labeled iPS-MLs to SCID mice bearing SK-MEL28 melanoma |
In vitro effects: tumor growth inhibition Therapeutic efficacy: an inhibition of tumor growth by iPS-ML/IFNα, iPS-ML/IFNβ, and iPS-ML/IFNα + iPS-ML/IFNβ Biodistribution / safety: iMphs are found in the tumors; no signs of malignancy from human iPS-MLs at week 12 post-transfer |
|
| Zhang et al. [133] | Healthy donor | Lentiviral transduction with anti-CD19 CAR and anti-mesothelin-CAR | In vivo: transplantation of CAR-Meso-iMphs activated in vitro by IFN-γ to NSG mice injected with ovarian cancer cells HO8910 |
Therapeutic efficacy: a reduction of tumor burden iMph persistence: CAR-iMphs persisted till more than 20 days and disappeared after day 30 |
|
| Bone formation | Jeon et al. [151] | Healthy donor | - |
In vitro: co-culture of iMphs with MSCs on scaffolds in osteogenic conditions; In vivo: s.c. transplantation of scaffolds seeded with MSCs and iMphs into nude mice |
In vitro & in vivo effects: an acceleration of bone formation Safety: no teratoma formation was observed around the site of the implant at week 8 post-transplantation |
| Liver fibrosis | Pouyanfard et al. [150] | Healthy donor | - | In vivo: transplantation to immunodeficient mice with liver fibrosis | Therapeutic efficacy: a reduction of the expression of fibrinogenic genes and histological disease markers |
ADA adenosine deaminase, AL-iMphs alveolar-like iMphs, BALF broncho-alveolar fluid, BALL-1 B-cell leukemia cell line, CAR chimeric antigen receptor, CSF2RA colony stimulating factor 2 receptor, CT computed tomography, iPS-ML iPSC-derived myeloid/macrophage cell line, MSC mesenchymal stem cells, PAP pulmonary alveolar proteinosis, PEG-ADA polyethylene glycol–conjugated ADA, WT wild type, scFv single chain variable region fragment