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Clinical and Experimental Medicine

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25.01.2022 | Short Communication

Mycobacterium bovis bacille Calmette–Guerin-derived extracellular vesicles as an alternative to live BCG immunotherapy

verfasst von: Patrick Gellings, Michelle Galeas-Pena, Lisa A. Morici

Erschienen in: Clinical and Experimental Medicine | Ausgabe 2/2023

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Abstract

For over 40 years, the gold standard treatment for non-muscular invasive bladder cancer (NMIBC) has been repeated administration of Mycobacterium bovis bacille Calmette–Guerin (BCG). Upon administration, BCG initiates a cascade of immunological events that lead to the recruitment of immune cells to the bladder that eliminates NMIBC cells in a multi-mechanistic, yet incompletely defined manner. Despite its effectiveness, live BCG immunotherapy is often impacted by limited supply and availability and can cause rare but serious side effects. Bacterial extracellular vesicles (EV) are nanoparticles secreted by live bacteria. EVs are composed of multiple surface proteins, sugars, and lipid that can elicit cellular responses and host recognition similar to live bacteria. In this study, we sought to evaluate the cellular responses of epithelial bladder cancer cells (BCC) to BCG EVs and live BCG. We compared the effect of each treatment on BCC cytokine production, cellular viability and apoptosis. Our data suggest that BCG EVs are as effective as live BCG in eliciting cytokine responses and halting cancer cell growth by, in part, inducing apoptosis. These results indicate that BCG EVs warrant investigation as an alternative to live BCG for NMIBC immunotherapy.

Graphical Abstract

Richters A, Aben KKH, Kiemeney LALM. The global burden of urinary bladder cancer: an update. World J Urol. 2020;38:1895–904. https://doi.org/10.1007/s00345-019-02984-4.CrossRefPubMed

Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66:271–289. https://doi.org/10.3322/caac.21349.

Pettenati C, Ingersoll MA. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol. 2018;15:615–25. https://doi.org/10.1038/s41585-018-0055-4.CrossRefPubMed

Isharwal S, Konety B. Non-muscle invasive bladder cancer risk stratification. Indian J Urol. 2015;31:289–96. https://doi.org/10.4103/0970-1591.166445.CrossRefPubMedPubMedCentral

Annels NE, Simpson GR, Pandha H. Modifying the non-muscle invasive bladder cancer immune microenvironment for optimal therapeutic response. Front Oncol. 2020;10:175. https://doi.org/10.3389/fonc.2020.00175.CrossRefPubMedPubMedCentral

van Puffelen JH, Keating ST, Oosterwijk E, et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat Rev Urol. 2020;17:513–25. https://doi.org/10.1038/s41585-020-0346-4.CrossRefPubMed

Janaszek-Seydlitz W, Prygiel M, Bucholc B, et al. Effect of different bacillus Calmette-Guerin substrains on growth inhibition of T24 bladder cancer cells and cytokines secretion by BCG activated peripheral blood mononuclear cells of PBMCs. Adv Clin Exp Med. 2014;23:877–84. https://doi.org/10.17219/acem/37330.CrossRefPubMed

Schwarzer K, Foerster M, Steiner T, et al. BCG strain S4-jena: an early BCG strain is capable to reduce the proliferation of bladder cancer cells by induction of apoptosis. Cancer Cell Int. 2010;10:21. https://doi.org/10.1186/1475-2867-10-21.CrossRefPubMedPubMedCentral

Chen F, Zhang G, Iwamoto Y, See WA. BCG directly induces cell cycle arrest in human transitional carcinoma cell lines as a consequence of integrin cross-linking. BMC Urol. 2005;5:8. https://doi.org/10.1186/1471-2490-5-8.CrossRefPubMedPubMedCentral

10.

Yu D-S, Wu C-L, Ping S-Y, Keng C, Shen K-H. Bacille Calmette-Guerin can induce cellular apoptosis of urothelial cancer directly through toll-like receptor 7 activation. Kaohsiung J Med Sci. 2015;31:391–7. https://doi.org/10.1016/j.kjms.2015.05.005.CrossRefPubMed

11.

Golla V, Lenis AT, Faiena I, Chamie K. Intravesical therapy for non-muscle invasive bladder cancer-current and future options in the age of bacillus Calmette-Guerin shortage. Rev Urol. 2019;21:145–53.PubMedPubMedCentral

12.

Guallar-Garrido S, Julián E. Bacillus Calmette-Guérin (BCG) therapy for bladder cancer: an update. Immunotargets Ther. 2020;9:1–11. https://doi.org/10.2147/ITT.S202006.CrossRefPubMedPubMedCentral

13.

Tan L, Testa G, Yung T. Diffuse alveolar damage in BCGosis: a rare complication of intravesical bacillus Calmette-Guérin therapy for transitional cell carcinoma. Pathology. 1999;31:55–6. https://doi.org/10.1080/003130299105566.CrossRefPubMed

14.

Mody GN, Tran V, Landman J. BCGosis: case report of intravesicular bacille Calmette-Guérin causing upper tract granulomas simulating a renal mass without evidence of ipsilateral vesicoureteral reflux. Urology. 2009;73(444):e9-10. https://doi.org/10.1016/j.urology.2008.02.037.CrossRef

15.

Green DB, Kawashima A, Menias CO, et al. Complications of intravesical BCG immunotherapy for bladder cancer. Radiographics. 2019;39:80–94. https://doi.org/10.1148/rg.2019180014.CrossRefPubMed

16.

Mehta AR, Mehta PR, Mehta RL. A cough conundrum in a patient with a previous history of BCG immunotherapy for bladder cancer. BMJ Case Rep. 2012. https://doi.org/10.1136/bcr-2012-007327.CrossRefPubMedPubMedCentral

17.

Lukacs S, Tschobotko B, Szabo NA, Symes A. Systemic BCG-osis as a rare side effect of intravesical BCG treatment for superficial bladder cancer. Case Rep Urol. 2013;2013:1–3. https://doi.org/10.1155/2013/821526.CrossRef

18.

Larsen BT, Smith ML, Grys TE, Vikram HR, Colby TV. Histopathology of disseminated mycobacterium bovis infection complicating intravesical BCG immunotherapy for urothelial carcinoma. Int J Surg Pathol. 2015;23:189–95. https://doi.org/10.1177/1066896914567332.CrossRefPubMed

19.

Smith DM. BCG-osis following intravesical BCG treatment leading to miliary pulmonary nodules, penile granulomas and a mycotic aortic aneurysm. BMJ Case Rep. 2016. https://doi.org/10.1136/bcr-2016-215635.CrossRefPubMedPubMedCentral

20.

Madentzoglou MS, Nathena D, Sinatkas V, Michalodimitrakis M, Kranioti EF. Lethal BCG-osis, in the context of superficial urothelial bladder carcinoma, diagnosed in autopsy. Egypt J Forensic Sci. 2016;6:284–8. https://doi.org/10.1016/j.ejfs.2015.07.007.CrossRef

21.

Liaw F, Tan YY, Hendry D. Systemic BCG-osis following intravesical BCG instillation for bladder carcinoma. Clin Case Rep. 2017;5:1569–72. https://doi.org/10.1002/ccr3.1129.CrossRefPubMedPubMedCentral

22.

Wadhwani A, Moore RD, Bakshi D, Mirakhur A. Mycotic aortic aneurysms post-intravesical BCG treatment for early-stage bladder carcinoma. CVIR Endovasc. 2018;1:28. https://doi.org/10.1186/s42155-018-0036-y.CrossRefPubMedPubMedCentral

23.

Ribeiro L, Rajendran S, Stenson K, Loftus I. Rare case of a proximal descending thoracic aorta mycotic aneurysm following intravesical BCG injections for the treatment of bladder cancer. BMJ Case Rep. 2019. https://doi.org/10.1136/bcr-2019-231595.CrossRefPubMedPubMedCentral

24.

Headlam J, Wheeler A, Yuen K, Brierley E, Todd OM. Disseminated bacillus Calmette-Guérin (BCG): a cause of delirium in an older adult. J R Coll Phys Edinb. 2020;50:152–5. https://doi.org/10.4997/JRCPE.2020.215.CrossRef

25.

Micoli F, MacLennan CA. Outer membrane vesicle vaccines. Semin Immunol. 2020;50:101433. https://doi.org/10.1016/j.smim.2020.101433.CrossRefPubMed

26.

Cecil JD, Sirisaengtaksin N, O’Brien-Simpson NM, Krachler AM. Outer membrane vesicle-host cell interactions. Microbiol Spectr. 2019. https://doi.org/10.1128/microbiolspec.PSIB-0001-2018.CrossRefPubMed

27.

Baker S, Davitt C, Motyka N, et al. Burkholderia pseudomallei outer membrane vesicle vaccine provides cross protection against inhalational glanders in mice and non-human primates. Vaccines. 2017;5:49. https://doi.org/10.3390/vaccines5040049.CrossRefPubMedPubMedCentral

28.

Nieves W, Petersen H, Judy BM, et al. A burkholderia pseudomallei outer membrane vesicle vaccine provides protection against lethal sepsis. Clin Vaccine Immunol. 2014;21:747–54. https://doi.org/10.1128/CVI.00119-14.CrossRefPubMedPubMedCentral

29.

Nieves W, Asakrah S, Qazi O, et al. A naturally derived outer-membrane vesicle vaccine protects against lethal pulmonary burkholderia pseudomallei infection. Vaccine. 2011;29:8381–9. https://doi.org/10.1016/j.vaccine.2011.08.058.CrossRefPubMedPubMedCentral

30.

Petersen H, Nieves W, Russell-Lodrigue K, Roy CJ, Morici LA. Evaluation of a burkholderia pseudomallei outer membrane vesicle vaccine in nonhuman primates. Procedia Vaccinol. 2014;8:38–42. https://doi.org/10.1016/j.provac.2014.07.007.CrossRefPubMedPubMedCentral

31.

van der Pol L, Stork M, van der Ley P. Outer membrane vesicles as platform vaccine technology. Biotechnol J. 2015;10:1689–706. https://doi.org/10.1002/biot.201400395.CrossRefPubMedPubMedCentral

32.

Tan K, Li R, Huang X, Liu Q. Outer membrane vesicles: current status and future direction of these novel vaccine adjuvants. Front Microbiol. 2018;9:783. https://doi.org/10.3389/fmicb.2018.00783.CrossRefPubMedPubMedCentral

33.

Kates M, Matoso A, Choi W, et al. Adaptive immune resistance to intravesical BCG in non-muscle invasive bladder cancer: implications for prospective BCG-unresponsive trials. Clin Cancer Res. 2020;26:882–91. https://doi.org/10.1158/1078-0432.CCR-19-1920.CrossRefPubMed

34.

Miyake M, Tatsumi Y, Gotoh D, et al. Regulatory T cells and tumor-associated macrophages in the tumor microenvironment in non-muscle invasive bladder cancer treated with intravesical bacille Calmette-Guérin: a long-term follow-up study of a Japanese cohort. IJMS. 2017;18:2186. https://doi.org/10.3390/ijms18102186.CrossRefPubMedPubMedCentral

35.

Suriano F, Santini D, Perrone G, et al. Tumor associated macrophages polarization dictates the efficacy of BCG instillation in non-muscle invasive urothelial bladder cancer. J Exp Clin Cancer Res. 2013;32:87. https://doi.org/10.1186/1756-9966-32-87.CrossRefPubMedPubMedCentral

36.

Adamkiewicz M, Bryniarski P, Kowalik M, Burzyński B, Rajwa P, Paradysz A. Lymphocyte-to-monocyte ratio is the independent prognostic marker of progression in patients undergoing bcg-immunotherapy for bladder cancer. Front Oncol. 2021;11:655000. https://doi.org/10.3389/fonc.2021.655000.CrossRefPubMedPubMedCentral

37.

Liu K, Sun E, Lei M, et al. BCG-induced formation of neutrophil extracellular traps play an important role in bladder cancer treatment. Clin Immunol. 2019;201:4–14. https://doi.org/10.1016/j.clim.2019.02.005.CrossRefPubMed

38.

Kamohara H, Matsuyama W, Shimozato O, et al. Regulation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and TRAIL receptor expression in human neutrophils. Immunology. 2004;111:186–94. https://doi.org/10.1111/j.0019-2805.2003.01794.x.CrossRefPubMedPubMedCentral

39.

Ratliff TL, Ritchey JK, Yuan JJ, Andriole GL, Catalona WJ. T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J Urol. 1993;150:1018–23. https://doi.org/10.1016/s0022-5347(17)35678-1.CrossRefPubMed

40.

Chen R. Culture and detection of mycobacterium tuberculosis (MTB) and mycobacterium bovis (BCG). BIO-PROTOCOL. (2012); https://doi.org/10.21769/BioProtoc.49.

41.

Gupta S, Marcela Rodriguez G. Isolation and characterization of extracellular vesicles produced by iron-limited mycobacteria. JoVE. 2109; https://doi.org/10.3791/60359.

42.

Bevers RF, de Boer EC, Kurth KH, Schamhart DH. BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines. Eur Cytokine Netw. 1998;9:181–6.PubMed

43.

de Reijke TM, Vos PCN, de Boer EC, et al. Cytokine production by the human bladder carcinoma cell line T24 in the presence of bacillus Calmette-Guerin (BCG). Urol Res. 1993;21:349–52. https://doi.org/10.1007/BF00296835.CrossRefPubMed

44.

Arruebo M, Vilaboa N, Sáez-Gutierrez B, et al. Assessment of the evolution of cancer treatment therapies. Cancers. 2011;3:3279–330. https://doi.org/10.3390/cancers3033279.CrossRefPubMedPubMedCentral

45.

Dobosz P, Dzieciątkowski T. The intriguing history of cancer immunotherapy. Front Immunol. 2019;10:2965. https://doi.org/10.3389/fimmu.2019.02965.CrossRefPubMedPubMedCentral

46.

Roma-Rodrigues C, Rivas-García L, Baptista PV, Fernandes AR. Gene therapy in cancer treatment: why go nano? Pharmaceutics. 2020;12:E233. https://doi.org/10.3390/pharmaceutics12030233.CrossRef

47.

Chu D-T, Nguyen TT, Tien NLB, et al. Recent progress of stem cell therapy in cancer treatment: molecular mechanisms and potential applications. Cells. 2020;9:E563. https://doi.org/10.3390/cells9030563.CrossRef

48.

Messing EM. The BCG shortage. Bladder Cancer. 2017;3:227–8. https://doi.org/10.3233/BLC-179018.CrossRefPubMedPubMedCentral

49.

Tian Y, Li S, Song J, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35:2383–90. https://doi.org/10.1016/j.biomaterials.2013.11.083.CrossRefPubMed

50.

Saari H, Lázaro-Ibáñez E, Viitala T, Vuorimaa-Laukkanen E, Siljander P, Yliperttula M. Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of paclitaxel in autologous prostate cancer cells. J Control Release. 2015;220:727–37. https://doi.org/10.1016/j.jconrel.2015.09.031.CrossRefPubMed

51.

Agrawal AK, Aqil F, Jeyabalan J, et al. Milk-derived exosomes for oral delivery of paclitaxel. Nanomed Nanotechnol Biol Med. 2017;13:1627–36. https://doi.org/10.1016/j.nano.2017.03.001.CrossRef

52.

Cabeza L, Perazzoli G, Peña M, et al. Cancer therapy based on extracellular vesicles as drug delivery vehicles. J Control Release. 2020;327:296–315. https://doi.org/10.1016/j.jconrel.2020.08.018.CrossRefPubMed

53.

Kiselyov A, Bunimovich-Mendrazitsky S, Startsev V. Treatment of non-muscle invasive bladder cancer with bacillus Calmette-Guerin (BCG): biological markers and simulation studies. BBA Clin. 2015;4:27–34. https://doi.org/10.1016/j.bbacli.2015.06.002.CrossRefPubMedPubMedCentral

54.

Zhang Y, Khoo HE, Esuvaranathan K. Effects of bacillus Calmette-Guerin and interferon-alpha-2B on human bladder cancer in vitro. Int J Cancer. 1997;71:851–7. https://doi.org/10.1002/(sici)1097-0215(19970529)71:5%3c851::aid-ijc25%3e3.0.co,2-9.CrossRefPubMed

55.

Zhang Y, Mahendran R, Yap LL, Esuvaranathan K, Khoo HE. The signalling pathway for BCG-induced interleukin-6 production in human bladder cancer cells. Biochem Pharmacol. 2002;63:273–82. https://doi.org/10.1016/s0006-2952(01)00831-0.CrossRefPubMed

56.

Morizawa Y, Miyake M, Shimada K, et al. Colony-stimulating factors detected in tumor cells and voided urine are potential prognostic markers for patients with muscle-invasive bladder cancer undergoing radical cystectomy. Res Rep Urol. 2018;10:103–11. https://doi.org/10.2147/RRU.S166497.CrossRefPubMedPubMedCentral

57.

Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22:8628–33. https://doi.org/10.1038/sj.onc.1207232.CrossRefPubMed

58.

Jinesh GG, Kamat AM. Redirecting neutrophils against bladder cancer cells by BCG and Smac mimetic combination. Oncoimmunology. 2012;1:1161–2. https://doi.org/10.4161/onci.20928.CrossRef

Titel: Mycobacterium bovis bacille Calmette–Guerin-derived extracellular vesicles as an alternative to live BCG immunotherapy
verfasst von: Patrick Gellings
Michelle Galeas-Pena
Lisa A. Morici
Publikationsdatum: 25.01.2022
Verlag: Springer International Publishing
Erschienen in: Clinical and Experimental Medicine / Ausgabe 2/2023
Print ISSN: 1591-8890
Elektronische ISSN: 1591-9528
DOI: https://doi.org/10.1007/s10238-022-00794-4

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