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Review
. 2016 Oct 28:240:527-540.
doi: 10.1016/j.jconrel.2016.07.018. Epub 2016 Jul 12.

Macrophage-based cell therapies: The long and winding road

Simon Lee  1 , Saul Kivimäe  2 , Aaron Dolor  2 , Francis C Szoka  3
Affiliations
Review

Macrophage-based cell therapies: The long and winding road

Simon Lee et al. J Control Release. .

Abstract

In the quest for better medicines, attention is increasingly turning to cell-based therapies. The rationale is that infused cells can provide a targeted therapy to precisely correct a complex disease phenotype. Between 1987 and 2010, autologous macrophages (MΦs) were used in clinical trials to treat a variety of human tumors; this approach provided a modest therapeutic benefit in some patients but no lasting remissions. These trials were initiated prior to an understanding of: the complexity of MΦ phenotypes, their ability to alter their phenotype in response to various cytokines and/or the environment, and the extent of survival of the re-infused MΦs. It is now known that while inflammatory MΦs can kill tumor cells, the tumor environment is able to reprogram MΦs into a tumorigenic phenotype; inducing blood vessel formation and contributing to a cancer cell growth-promoting milieu. We review how new information enables the development of large numbers of ex vivo generated MΦs, and how conditioning and gene engineering strategies are used to restrict the MΦ to an appropriate phenotype or to enable production of therapeutic proteins. We survey applications in which the MΦ is loaded with nanomedicines, such as liposomes ex vivo, so when the drug-loaded MΦs are infused into an animal, the drug is released at the disease site. Finally, we also review the current status of MΦ biodistribution and survival after transplantation into an animal. The combination of these recent advances opens the way for improved MΦ cell therapies.

Keywords: Cell polarization; Cell therapy; Drug delivery; Gene editing; Macrophages.

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Conflict of interest statement

The authors do not have conflicts of interest to report.

Figures

Figure 1
Figure 1
Tissue-resident macrophages can be found throughout the body in virtually all tissues and organs. These macrophages perform a variety of tasks including phagocytosis of dead cells and debris, modulating innate immune responses, maintaining homeostatic growth, repair and metabolism. Macrophages from different tissues have distinct gene expression profiles, but in some cases, due to phenotypic plasticity, macrophages from one tissue can be transplanted to another and adopt the new tissue-resident profile [33].
Figure 2
Figure 2
Therapeutic macrophages collected from human blood via leukapheresis and elutriation. Monocytes are purified from blood via leukapheresis and elutriation, followed by culture in Teflon bags. Monocytes proliferate and differentiate in media with cytokines (IFNγ and GM-CSF) over a period of 7–10 days, generating up to 107-109 cells per patient.
Figure 3
Figure 3
Modeling of macrophage uptake of drug particles shows a theoretical uptake of 10–100 µg per 106 cells. Drug uptake is a function of number of particles phagocytosed (nparticles), drug particle radius (r), drug density (ρdrug) and packing factor (PF -percentage of particle that is drug). Based on the equation, theoretical drug loading is presented as a function of nparticles, r and ρdrug at PF values of 0.1 (blue), 0.5 (red) and 1 (green).
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