Engineering New Immunotherapies against Cancer using Bacterial Outer Membrane Vesicles and Supported by Preclinical Data

Main Article Content

James E. Galen Thanh Pham

Abstract

Cancer remains a serious challenge to public health, with breast cancer, lung, and colorectal cancers predominating in both incidence and deaths worldwide. Significant advances have been made in the therapeutic treatment and resolution of non-solid tumors using immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell therapy to break immune tolerance and initiate tumor clearance. However, these innovative strategies have enjoyed only limited success with solid tumors, especially in late-stage cancers in which tumor size is large. An immunosuppressive tumor microenvironment (TME) that surrounds and protects solid tumors significantly confounds the ability of the host immune system to target and eliminate tumor tissue. Novel technologies using nanomedicines have begun to yield promising results by penetrating into the microenvironment to stimulate innate immunity and induce trafficking of activated antigen presenting cells to regional lymph nodes, ultimately leading to tumor-specific adaptive immune responses. One type of nanomedicine that is generating increasing enthusiasm in the field of immunotherapy are bacterial outer membrane vesicles (OMVs) that can be genetically engineered to surface-express tumor-associated antigens; the resulting recombinant OMVs (rOMVs) can then be purified as immunotherapeutic vaccines. Recent data from experimental animal models have demonstrated remarkable efficacy in tumor challenge models. Such promising experiments suggest the possibility of translating these novel strategies into success with solid tumors in clinical trials. In this review, we will summarize current research using purified rOMVs as immunotherapeutic vaccines and further discuss potential obstacles that still need to be adequately addressed to ensure success in human trials.

Article Details

How to Cite
GALEN, James E.; PHAM, Thanh. Engineering New Immunotherapies against Cancer using Bacterial Outer Membrane Vesicles and Supported by Preclinical Data. Medical Research Archives, [S.l.], v. 10, n. 7, july 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2895>. Date accessed: 08 aug. 2022. doi: https://doi.org/10.18103/mra.v10i7.2895.
Section
Research Articles

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. May 2021;71(3):209-249.
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. Jan 2022;72(1):7-33.
3. Lynch D, Murphy A. The emerging role of immunotherapy in colorectal cancer. Ann Transl Med. Aug 2016;4(16):305.
4. Kather JN, Halama N. Harnessing the innate immune system and local immunological microenvironment to treat colorectal cancer. Br J Cancer. Apr 2019;120(9):871-882.
5. IJsselsteijn M, Sanz-Pamplona R, Hermitte F, de Miranda N. Colorectal cancer: A paradigmatic model for cancer immunology and immunotherapy. Mol Aspects Med. Oct 2019;69:123-129.
6. Irvine DJ, Dane EL. Enhancing cancer immunotherapy with nanomedicine. Nat Rev Immunol. May 2020;20(5):321-334.
7. Peña-Romero AC, Orenes-Piñero E. Dual Effect of Immune Cells within Tumour Microenvironment: Pro- and Anti-Tumour Effects and Their Triggers. Cancers (Basel). Mar 25 2022;14(7).
8. van der Burg SH, Arens R, Ossendorp F, van Hall T, Melief CJ. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer. Apr 2016;16(4):219-233.
9. Baeza A. Tumor Targeted Nanocarriers for Immunotherapy. Molecules. Mar 26 2020;25(7).
10. Fu C, Jiang A. Dendritic Cells and CD8 T Cell Immunity in Tumor Microenvironment. Front Immunol. 2018;9:3059.
11. Bejarano L, Jordāo MJC, Joyce JA. Therapeutic Targeting of the Tumor Microenvironment. Cancer Discov. Apr 2021;11(4):933-959.
12. Woo SR, Corrales L, Gajewski TF. Innate immune recognition of cancer. Annu Rev Immunol. 2015;33:445-474.
13. Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. Jun 2021;21(6):360-378.
14. Hinshaw DC, Shevde LA. The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. Sep 15 2019;79(18):4557-4566.
15. Zhu SY, Yu KD. Breast Cancer Vaccines: Disappointing or Promising? Front Immunol. 2022;13:828386.
16. Saeed M, Gao J, Shi Y, Lammers T, Yu H. Engineering Nanoparticles to Reprogram the Tumor Immune Microenvironment for Improved Cancer Immunotherapy. Theranostics. 2019;9(26):7981-8000.
17. Haegebaert RMS, Kempers M, Ceelen W, Lentacker I, Remaut K. Nanoparticle mediated targeting of toll-like receptors to treat colorectal cancer. Eur J Pharm Biopharm. Mar 2022;172:16-30.
18. Melero I, Gaudernack G, Gerritsen W, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. Sep 2014;11(9):509-524.
19. Silveira MJ, Castro F, Oliveira MJ, Sarmento B. Immunomodulatory nanomedicine for colorectal cancer treatment: a landscape to be explored? Biomater Sci. May 4 2021;9(9):3228-3243.
20. Garg AD, Dudek-Peric AM, Romano E, Agostinis P. Immunogenic cell death. Int J Dev Biol. 2015;59(1-3):131-140.
21. Fucikova J, Spisek R, Kroemer G, Galluzzi L. Calreticulin and cancer. Cell Res. Jan 2021;31(1):5-16.
22. Kelly HG, Kent SJ, Wheatley AK. Immunological basis for enhanced immunity of nanoparticle vaccines. Expert Rev Vaccines. Mar 2019;18(3):269-280.
23. Grant SM, Lou M, Yao L, Germain RN, Radtke AJ. The lymph node at a glance - how spatial organization optimizes the immune response. J Cell Sci. Mar 6 2020;133(5).
24. Moyer TJ, Zmolek AC, Irvine DJ. Beyond antigens and adjuvants: formulating future vaccines. J Clin Invest. Mar 1 2016;126(3):799-808.
25. Irvine DJ, Aung A, Silva M. Controlling timing and location in vaccines. Adv Drug Deliv Rev. 2020;158:91-115.
26. Nooraei S, Bahrulolum H, Hoseini ZS, et al. Virus-like particles: preparation, immunogenicity and their roles as nanovaccines and drug nanocarriers. J Nanobiotechnology. Feb 25 2021;19(1):59.
27. Bachmann MF, Jennings GT. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol. Nov 2010;10(11):787-796.
28. Fang J, Islam W, Maeda H. Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers. Adv Drug Deliv Rev. 2020;157:142-160.
29. Kim J, Archer PA, Thomas SN. Innovations in lymph node targeting nanocarriers. Semin Immunol. Aug 2021;56:101534.
30. Li M, Zhou H, Yang C, et al. Bacterial outer membrane vesicles as a platform for biomedical applications: An update. J Control Release. Jul 10 2020;323:253-268.
31. Kulp A, Kuehn MJ. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu Rev Microbiol. 2010;64:163-184.
32. Schwechheimer C, Kuehn MJ. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol. Oct 2015;13(10):605-619.
33. Wallace AJ, Stillman TJ, Atkins A, et al. E. coli hemolysin E (HlyE, ClyA, SheA): X-ray crystal structure of the toxin and observation of membrane pores by electron microscopy. Cell. 2000;100:265-276.
34. Wai SN, Lindmark B, Soderblom T, et al. Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin. Cell. 2003;115(1):25-35.
35. Galen JE, Zhao L, Chinchilla M, et al. Adaptation of the endogenous Salmonella enterica serovar Typhi clyA-encoded hemolysin for antigen export enhances the immunogenicity of anthrax protective antigen domain 4 expressed by the attenuated live-vector vaccine strain CVD 908-htrA. Infect Immun. 2004;72(12):7096-7106.
36. Chen DJ, Osterrieder N, Metzger SM, et al. Delivery of foreign antigens by engineered outer membrane vesicle vaccines. Proc Natl Acad Sci U S A. Feb 16 2010;107(7):3099-3104.
37. Murase K. Cytolysin A (ClyA): A Bacterial Virulence Factor with Potential Applications in Nanopore Technology, Vaccine Development, and Tumor Therapy. Toxins (Basel). Jan 21 2022;14(2).
38. Li L, Fierer JO, Rapoport TA, Howarth M. Structural analysis and optimization of the covalent association between SpyCatcher and a peptide Tag. J Mol Biol. Jan 23 2014;426(2):309-317.
39. Yue Y, Xu J, Li Y, et al. Antigen-bearing outer membrane vesicles as tumour vaccines produced in situ by ingested genetically engineered bacteria. Nat Biomed Eng. May 2 2022.
40. Golombek SK, May JN, Theek B, et al. Tumor targeting via EPR: Strategies to enhance patient responses. Adv Drug Deliv Rev. May 2018;130:17-38.
41. Kubes P, Jenne C. Immune Responses in the Liver. Annu Rev Immunol. Apr 26 2018;36:247-277.
42. Nichols JW, Bae YH. Odyssey of a cancer nanoparticle: from injection site to site of action. Nano Today. Dec 1 2012;7(6):606-618.
43. Poon W, Zhang YN, Ouyang B, et al. Elimination Pathways of Nanoparticles. ACS Nano. May 28 2019;13(5):5785-5798.
44. Overchuk M, Zheng G. Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics. Biomaterials. Feb 2018;156:217-237.
45. Lewis SM, Williams A, Eisenbarth SC. Structure and function of the immune system in the spleen. Sci Immunol. Mar 1 2019;4(33).
46. Kingston BR, Lin ZP, Ouyang B, et al. Specific Endothelial Cells Govern Nanoparticle Entry into Solid Tumors. ACS Nano. Sep 28 2021;15(9):14080-14094.
47. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. Dec 1986;46(12 Pt 1):6387-6392.
48. Wu J. The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application. J Pers Med. Aug 6 2021;11(8).
49. Bikorimana JP, Salame N, Beaudoin S, et al. Promoting antigen escape from dendritic cell endosomes potentiates anti-tumoral immunity. Cell Rep Med. Mar 15 2022;3(3):100534.
50. Schetters STT, Jong WSP, Horrevorts SK, et al. Outer membrane vesicles engineered to express membrane-bound antigen program dendritic cells for cross-presentation to CD8(+) T cells. Acta Biomater. Jun 2019;91:248-257.
51. Nijen Twilhaar MK, Czentner L, Bouma RG, et al. Incorporation of Toll-Like Receptor Ligands and Inflammasome Stimuli in GM3 Liposomes to Induce Dendritic Cell Maturation and T Cell Responses. Front Immunol. 2022;13:842241.
52. Kim OY, Park HT, Dinh NTH, et al. Bacterial outer membrane vesicles suppress tumor by interferon-γ-mediated antitumor response. Nat Commun. Sep 20 2017;8(1):626.
53. Matsuura M. Structural Modifications of Bacterial Lipopolysaccharide that Facilitate Gram-Negative Bacteria Evasion of Host Innate Immunity. Front Immunol. 2013;4:109.
54. Qing S, Lyu C, Zhu L, et al. Biomineralized Bacterial Outer Membrane Vesicles Potentiate Safe and Efficient Tumor Microenvironment Reprogramming for Anticancer Therapy. Adv Mater. Nov 2020;32(47):e2002085.
55. Cheng K, Zhao R, Li Y, et al. Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology. Nat Commun. Apr 6 2021;12(1):2041.
56. Brune KD, Leneghan DB, Brian IJ, et al. Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization. Sci Rep. Jan 19 2016;6:19234.
57. Islam W, Kimura S, Islam R, et al. EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect. J Pers Med. May 28 2021;11(6).
58. Dhaliwal A, Zheng G. Improving accessibility of EPR-insensitive tumor phenotypes using EPR-adaptive strategies: Designing a new perspective in nanomedicine delivery. Theranostics. 2019;9(26):8091-8108.
59. Maeda H. The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery-Personal Remarks and Future Prospects. J Pers Med. Mar 22 2021;11(3).
60. Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. Jul 1993;10(7):1093-1095.
61. Tulkens J, Vergauwen G, Van Deun J, et al. Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut. Jan 2020;69(1):191-193.
62. Tulkens J, De Wever O, Hendrix A. Analyzing bacterial extracellular vesicles in human body fluids by orthogonal biophysical separation and biochemical characterization. Nat Protoc. Jan 2020;15(1):40-67.
63. Toso JF, Gill VJ, Hwu P, et al. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J.Clin.Oncol. 2002;20(1):142-152.
64. Heimann DM, Rosenberg SA. Continuous intravenous administration of live genetically modified salmonella typhimurium in patients with metastatic melanoma. J Immunother. Mar-Apr 2003;26(2):179-180.
65. Bertani B, Ruiz N. Function and Biogenesis of Lipopolysaccharides. EcoSal Plus. Aug 2018;8(1).
66. Elhenawy W, Bording-Jorgensen M, Valguarnera E, Haurat MF, Wine E, Feldman MF. LPS Remodeling Triggers Formation of Outer Membrane Vesicles in Salmonella. MBio. Jul 12 2016;7(4):pii: e00940-00916. doi: 00910.01128/mBio.00940-00916.
67. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. Apr 1999;9(2):67-81.
68. Bramswig KH, Poettler M, Unseld M, et al. Soluble carcinoembryonic antigen activates endothelial cells and tumor angiogenesis. Cancer Res. Nov 15 2013;73(22):6584-6596.
69. Cascio S, Finn OJ. Intra- and Extra-Cellular Events Related to Altered Glycosylation of MUC1 Promote Chronic Inflammation, Tumor Progression, Invasion, and Metastasis. Biomolecules. Oct 13 2016;6(4).
70. von Mensdorff-Pouilly S, Kinarsky L, Engelmann K, et al. Sequence-variant repeats of MUC1 show higher conformational flexibility, are less densely O-glycosylated and induce differential B lymphocyte responses. Glycobiology. Aug 2005;15(8):735-746.
71. Engelmann K, Baldus SE, Hanisch FG. Identification and topology of variant sequences within individual repeat domains of the human epithelial tumor mucin MUC1. J Biol Chem. Jul 27 2001;276(30):27764-27769.
72. Kawasaki K, Ernst RK, Miller SI. 3-O-deacylation of lipid A by PagL, a PhoP/PhoQ-regulated deacylase of Salmonella typhimurium, modulates signaling through Toll-like receptor 4. J Biol Chem. May 7 2004;279(19):20044-20048.
73. Zhao J, Raetz CR. A two-component Kdo hydrolase in the inner membrane of Francisella novicida. Mol Microbiol. Nov 2010;78(4):820-836.
74. Zhao J, An J, Hwang D, et al. The Lipid A 1-Phosphatase, LpxE, Functionally Connects Multiple Layers of Bacterial Envelope Biogenesis. mBio. Jun 18 2019;10(3).