Table 3 The development of approaches for iMph-based cell therapy

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