Are “backpack” armed macrophages the next big thing in cellular immunotherapy?
Image credit: https://wyss.harvard.edu/news/backpacks-boost-immune-cells-ability-to-kill-cancer/
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- in vitro, about 87% of the cells picked up one to four backpacks on their surfaces, which remained there for at least five days without being consumed and secreted IFNγ for at least 60 hours.
- when tested for various markers (iNOS, MHC-II and CD80) that are indicative of pro-inflammatory (M1) state -meaning that they have retained their cancer-killing tendencies- the macrophages carrying IFNγ backpacks expressed these three M1-associated traits much more strongly than macrophages with blank backpacks or macrophages in the presence of free IFNγ
- on the other side, the markers for anti-inflammatory (and hence pro-tumour) M2 state were not found to be significantly increased. VEGF, HIF-1α, and CD206 were the three markers examined for which the changes were less substantial than those observed for M1 markers, and the relative expression of all three M2 markers returned to values near the expression of untreated controls after 5 days.
- -in vivo (and this is where the real test was), macrophages carrying IFNγ backpacks expressed M1 indicators for at least 48 hours, and their expression levels were significantly higher than that of injected cells with blank backpacks or with free IFNγ. Also, the therapy treated mice had fewer metastatic nodules and smaller tumours than control mice, and they lived longer!
- Could we use this approach to do the opposite of what these researchers did, and shift macrophages into an anti-inflammatory state in patients with excess inflammation like rheumatoid arthritis, and Crohn’s disease?
- Could we load other antigens and cytokines and use this method in other types of circulatory cells beyond macrophage?
- Could we design even more efficient backpacks with other alternative biocompatible polymers?
A. N. Miliotou, L. C. Papadopoulou , CAR T-cell therapy: A new era in cancer immunotherapy. Curr. Pharm. Biotechnol. 19, 5–18 (2018).
G. Hucks, S. R. Rheingold, The journey to CAR T cell therapy: The pediatric and young adult experience with relapsed or refractory B-ALL. Blood Cancer J. 9, 10 (2019).
S. Lee, S. Kivimäe, A. Dolor, F. C. Szoka, Macrophage-based cell therapies: The long and winding road. J. Control. Release 240, 527–540 (2016)
Shields, C. W., Evans, M. A., Wang, L. L.-W., Baugh, N., Iyer, S., Wu, D., Zhao, Z., Pusuluri, A., Ukidve, A., Pan, D. C., & Mitragotri, S. (2020). Cellular backpacks for macrophage immunotherapy. Science Advances, 6(18), eaaz6579. https://doi.org/10.1126/sciadv.aaz6579
Doshi, N., Swiston, A. J., Gilbert, J. B., Alcaraz, M. L., Cohen, R. E., Rubner, M. F., & Mitragotri, S. (2011). Cell-Based Drug Delivery Devices Using Phagocytosis-Resistant Backpacks. Advanced Materials, 23(12), H105–H109. https://doi.org/10.1002/adma.201004074
Schroder, K., Hertzog, P.J., Ravasi, T. and Hume, D.A. (2004), Interferon‐γ: an overview of signals, mechanisms and functions. Journal of Leukocyte Biology, 75: 163-189. https://doi.org/10.1189/jlb.0603252
Materials that can be used to construct the backpack
- Inorganic materials such as gold or
- Iron oxide and quantum dots have also been used.
- AutoAg-coupled splenocyte (Ag-SPs) carriers have shown tolerance to autoAg in Th1/17-mediated autoimmune models of autoimmune encephalomyelitis (EAE), a mouse model of MS, and the model of type 1 diabetes (T1D). Instead of splenocytes, other cell types can be used to target specific diseases.
- Mice treated with small poly(maleic anhydride-alt-1-octadecene)-coated particles induced tolerance via liver sinusoidal endothelial cells and showed higher Tregs.
- Other synthetic biodegradable polymers - poly[methyl methacrylate], PVMA; poly[anhydride] NPs, PHE; poly[hydroxyethyl] aspartamide.
- Chitosan is a natural mucoadhesive polysaccharide known for its biocompatibility, biodegradability, nontoxic nature, and its ability to enhance the penetration of macromolecules across the mucosa. Intranasal mite allergen encapsulated in chitosan microparticles in sensitized mice attenuated bronchial hyperreactivity, lung inflammation, and mucus production. Chitosan microparticles also show an immunomodulatory effect during sublingual immunization in a model of allergic airway inflammation.
- PHEA (a,b-poly[N-2-hydroxyethyl]-DL-aspartamide) loaded with pollen extracts has shown promise.
Yeste A, Nadeau M, Burns EJ, Weiner HL, Quintana FJ. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc Natl Acad Sci [Internet]. 2012 Jul 10;109(28):11270–5. Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.1120611109
Yeste A, Takenaka MC, Mascanfroni ID, Nadeau M, Kenison JE, Patel B, et al. Tolerogenic nanoparticles inhibit T cell–mediated autoimmunity through SOCS2. Sci Signal [Internet]. 2016 Jun 21;9(433):ra61–ra61. Available from: https://stke.sciencemag.org/lookup/doi/10.1126/scisignal.aad0612
Carambia A, Freund B, Schwinge D, Bruns OT, Salmen SC, Ittrich H, et al. Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice. J Hepatol [Internet]. 2015 Jun;62(6):1349–56. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0168827815000112
Turley DM, Miller SD. Peripheral Tolerance Induction Using Ethylenecarbodiimide-Fixed APCs Uses both Direct and Indirect Mechanisms of Antigen Presentation for Prevention of Experimental Autoimmune Encephalomyelitis. J Immunol [Internet]. 2007 Feb 15;178(4):2212–20. Available from: http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.178.4.2212
Prasad S, Kohm AP, McMahon JS, Luo X, Miller SD. Pathogenesis of NOD diabetes is initiated by reactivity to the insulin B chain 9-23 epitope and involves functional epitope spreading. J Autoimmun [Internet]. 2012 Dec;39(4):347–53. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0896841112000480
Pearson RM, Casey LM, Hughes KR, Miller SD, Shea LD. In vivo reprogramming of immune cells: Technologies for induction of antigen-specific tolerance. Adv Drug Deliv Rev [Internet]. 2017 May;114:240–55. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0169409X17300406
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol [Internet]. 2007 Sep 17;7(9):715–25. Available from: http://www.nature.com/articles/nri2155
Nimmerjahn F, Ravetch J V. FcγRs in Health and Disease. In 2010. p. 105–25. Available from: http://link.springer.com/10.1007/82_2010_86
Krishnamoorthy S, Liu T, Drager D, Patarroyo-White S, Chhabra ES, Peters R, et al. Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice. Cell Immunol [Internet]. 2016 Mar;301:30–9. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0008874915300496
Licciardi M, Montana G, Bondì ML, Bonura A, Scialabba C, Melis M, et al. An allergen-polymeric nanoaggregate as a new tool for allergy vaccination. Int J Pharm [Internet]. 2014 Apr;465(1–2):275–83. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0378517314000520