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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/

Subash Chapagain
Subash Chapagain Nov 30, 2020

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[4]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

[5]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

[6]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

Creative contributions

Materials that can be used to construct the backpack

Shubhankar Kulkarni
Shubhankar Kulkarni Dec 16, 2020

[1]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

[2]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

[3]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

[4]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

[5]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

[6]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

[7]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

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[9]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

[10]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

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General comments

Shubhankar Kulkarni
Shubhankar Kulkarni3 months ago
A few other questions:
1. Is this a preventive therapy? If yes, I imagine the therapy will be needed to be given perpetually (since the life of the backpack is about 5 days? So, is a constitutive pro-inflammatory state advisable? Since you mention that anti-inflammatory molecules can be used to treat inflammatory diseases, will the pro-inflammatory ones lead to those same diseases?
2. Do these backpacks accumulate in different organs in the body? Since they are synthetic, they might create additional problems. Are they thrown out by the body in some way? If yes, that solves our problem.
Subash Chapagain
Subash Chapagain3 months ago
Shubhankar Kulkarni The approach seems to be more likely to be curative rather than preventive (however it would be interesting to see if we could load a certain portion of individual's macrophages beforehand and then try to see how much of preventive effects they might have which can surely be tested in mouse models if I am not wrong). In the context of carcinomas, it indeed would be crucial to objectify the scales to which the specific pro or anti-inflammatory molecules would give the presumed effects like you said.

As far as the bio-accumulation is concerned, they have reported no significant complexities related to it; the particles have been deemed absolutely biocompatible.