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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/

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Subash Chapagain
Subash Chapagain Nov 30, 2020
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Adoptive cell therapy (also referred to as cellular immunotherapy) aims at using cells of our immune system to eliminate different types of cancer. Classically brought into the picture of clinical implications by using T-cells that express chimeric antigen receptors (CARs), CAR T-cell therapies indicated a landmark in cancer therapy with a promise of full recovery in over 90% of patients with some of the blood-borne (liquid) cancers . Nevertheless, CAR T cell therapy is constrained in its scope due to the requirement of a priori knowledge and presence of tumour-specific antigens; its proven efficacy limited only to non-solid tumours, and a larger time frame (needs several weeks to prepare and expand the cells that can be used) .

Macrophages, owing to their ability to kill tumor cells where tumor-specific antigens are less (or even unknown), can hence come handy to overcome these shortcomings of the T cell therapies . Macrophages are the cells of the immune system that patrol the body, looking out for potential ‘foreign’ threats like viruses, bacteria and cancer cells, engulfing and destroying them upon encounter. What makes macrophages even more suitable candidates against tumours is the fact that tumour-associated macrophages (TAMs) form approximately 50% of the tumour mass.

Despite the potential, one persistent problem had bugged researchers for long while trying to extract macrophages from the body and use them extensively for tumor-killing:
the tumours secrete substances that signal the approaching macrophages from their tumor-killing state to a tumor-promoting state, rendering the attempts futile.

With a research study at Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS), this problem has seemingly been proved to be a solvable one . Building upon their another finding dated back to 2011 , the team has proven that small, discoidal particles of size within 10 um (width) can basically ride on macrophages, and provide a sustained anti-tumor stimulus for a long time without triggering the “eat me” response in macrophages; hence dictating their behaviour.

What exactly are these “backpacks”?

These are small disc-shaped particles constructed by using two layers of biocompatible polymer poly(lactic-co-glycolic) acid (PLGA), inside which a ‘filling’ of polyvinyl alcohol (PVA) and the cytokine interferon-gamma (IFNγ) are sandwiched. IFNγ was chosen because it is known as a potent stimulator of pro-inflammatory response in macrophages and in a number of tumours reported to reduce their sizes . To make the backpacks more cell-adherent, a cell-adhesive layer was added in the end.

Here are some revealing features of these backpack’s potential in anti-tumour activities, as reported in the paper:

  • 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!
All of these findings definitely are exciting, and the positive results have markedly opened up a new frontier in similar therapeutic approaches that can be devised in future. So, here are some questions that we can start to ask:
  1. 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?
  2. Could we load other antigens and cytokines and use this method in other types of circulatory cells beyond macrophage?
  3. Could we design even more efficient backpacks with other alternative biocompatible polymers?

[1]A. N. Miliotou, L. C. Papadopoulou , CAR T-cell therapy: A new era in cancer immunotherapy. Curr. Pharm. Biotechnol. 19, 5–18 (2018).

[2]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).

[3]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)

[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

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Creative contributions

Materials that can be used to construct the backpack

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Shubhankar Kulkarni
Shubhankar Kulkarni Dec 16, 2020
Apart from the biocompatible polymer poly(lactic-co-glycolic) acid (PLGA), here are a few other materials that have been used to encapsulate and deliver biomaterials to target cells in the body:
  1. Inorganic materials such as gold or
  2. Iron oxide and quantum dots have also been used.
  3. 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.
  4. Mice treated with small poly(maleic anhydride-alt-1-octadecene)-coated particles induced tolerance via liver sinusoidal endothelial cells and showed higher Tregs.
  5. Other synthetic biodegradable polymers - poly[methyl methacrylate], PVMA; poly[anhydride] NPs, PHE; poly[hydroxyethyl] aspartamide.
  6. 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.
  7. PHEA (a,b-poly[N-2-hydroxyethyl]-DL-aspartamide) loaded with pollen extracts has shown promise.

[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

[8]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

[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

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Shubhankar Kulkarni
Shubhankar Kulkarni3 years 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.
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Subash Chapagain
Subash Chapagain3 years 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.
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