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Langenbeck's Archives of Surgery

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Open Access 01-04-2012 | Review Article

Bacterial immunotherapy of gastrointestinal tumors

Authors: Michael Linnebacher, Claudia Maletzki, Ulrike Klier, Ernst Klar

Published in: Langenbeck's Archives of Surgery | Issue 4/2012

Abstract

Background

Cancer immunotherapy using bacteria dates back over 150 years. The deeper understanding on how the immune system interferes with the tumor microenvironment has led to the re-emergence of bacteria or their related products in immunotherapeutic concepts. In this review, we discuss recent approaches on experimental bacteriolytic therapy, emphasizing the specific interplay between bacteria, immune cells and tumor cells to break the tumor-induced tolerance.

Results

Experimental research during the last decades demonstrated beneficial but also adverse influence of bacteria on tumor growth. There is a strong correlation between chronic infections and tumor incidence. However, acute bacterial infections have favourable effects on tumor growth often contributing to complete remission. Tumor regression is usually attributable to both direct tumor cell killing (via apoptosis and/or necrosis, depending on the applied bacteria) and indirect immune stimulation. This includes (I) elimination of immunosuppressive immune cells (i.e. tumor-associated macrophages, myeloid-derived suppressor, and regulatory T cells), (II) suppression of Th2-directed cytokine secretion (TGFα, IL10), (III) providing a pro-inflammatory micro-milieu (tumor infiltrating neutrophils) and (IV) supporting the influx of cytotoxic T cells into tumors. This finally forces the development of an immunological memory and may provide long-term protection against cancer.

Conclusion

Immunotherapy using bacteria is still a double-edged sword. Experiences from the last years have substantially contributed to when bacteria and defined components thereof might be integrated into immunotherapeutic concepts. Attempts in transferring this approach into the clinics are on their way.

Tlaskalová-Hogenová H, Tucková L, Lodinová-Zádniková R et al (2002) Mucosal immunity: its role in defense and allergy. Int Arch Allergy Immunol 128:77–89PubMedCrossRef

Kosiewicz MM, Zirnheld AL, Alard P (2011) Gut microbiota, immunity, and disease: a complex relationship. Front Microbiol 2:180PubMed

Zhao M, Yang M, Ma H, Li X, Tan X, Li S, Yang Z, Hoffman RM (2006) Targeted therapy with a Salmonella typhimurium leucine–arginine auxotroph cures orthotopic human breast tumors in nude mice. Cancer Res 66:7647–7652PubMedCrossRef

Maletzki C, Linnebacher M, Kreikemeyer B, Emmrich J (2008) Pancreatic cancer regression by intratumoural injection of live Streptococcus pyogenes in a syngeneic mouse model. Gut 57:483–491PubMedCrossRef

Baban CK, Cronin M, O'Hanlon D, O'Sullivan GC, Tangney M (2010) Bacteria as vectors for gene therapy of cancer. Bioeng Bugs 1:385–394PubMedCrossRef

Sautès-Fridman C, Cherfils-Vicini J, Damotte D, Fisson S, Fridman WH, Cremer I, Dieu-Nosjean MC (2011) Tumor microenvironment is multifaceted. Cancer Metastasis Rev 30:13–25PubMedCrossRef

McCarthy EF (2006) The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J 26:154–158PubMed

Busch W (1868) Aus der Sitzung der medicinischen Section vom 13 November 1867. Berl Klin Wochenschr 5:137

Fehleisen F (1882) Ueber die Züchtung der Erysipelkokken auf künstlichem Nährboden und ihre Übertragbarkeit auf den Menschen. Dtsch Med Wochenschr 8:553–554CrossRef

10.

Wiemann B, Starnes CO (1994) Coley's toxins, tumor necrosis factor and cancer research: a historical perspective. Pharmacol Ther 64:529–564PubMedCrossRef

11.

Hobohm U (2001) Fever and cancer in perspective. Cancer Immunol Immunother 50:391–396PubMed

12.

Zacharski LR, Sukhatme VP (2005) Coley's toxin revisited: immunotherapy or plasminogen activator therapy of cancer? J Thromb Haemost 3:424–427PubMedCrossRef

13.

Marth E, Möse JR (1987) Oncolysis by Clostridium oncolyticum M55 and subsequent enzymatic determination of sialic acid in serum. Zentralbl Bakteriol Mikrobiol Hyg A 265:33–44PubMed

14.

Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B (2001) Combination bacteriolytic therapy for the treatment of experimental tumors. Proc Natl Acad Sci U S A 98:15155–15160PubMedCrossRef

15.

Taniguchi S, Fujimori M, Sasaki T, Tsutsui H, Shimatani Y, Seki K, Amano J (2010) Targeting solid tumors with non-pathogenic obligate anaerobic bacteria. Cancer Sci 101:1925–1932PubMedCrossRef

16.

Kizaka-Kondoh S, Inoue M, Harada H, Hiraoka M (2003) Tumor hypoxia: a target for selective cancer therapy. Cancer Sci 94:1021–1028PubMedCrossRef

17.

Schmidt W, Fabricius EM, Schneeweiss U (2006) The tumour–Clostridium phenomenon: 50 years of developmental research (review). Int J Oncol 29:1479–1492PubMed

18.

Agrawal N, Bettegowda C, Cheong I et al (2004) Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proc Natl Acad Sci U S A 101:15172–15177PubMedCrossRef

19.

Yazawa K, Fujimori M, Nakamura T, Sasaki T, Amano J, Kano Y, Taniguchi S (2001) Bifidobacterium longum as a delivery system for gene therapy of chemically induced rat mammary tumors. Breast Cancer Res Treat 66:165–170PubMedCrossRef

20.

Diaz LA Jr, Cheong I, Foss CA (2005) Pharmacologic and toxicologic evaluation of C. novyi-NT spores. Toxicol Sci 88:562–575PubMedCrossRef

21.

Bettegowda C, Dang LH, Abrams R et al (2003) Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria. Proc Natl Acad Sci U S A 100:15083–15088PubMedCrossRef

22.

Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341–352PubMedCrossRef

23.

Harada H (2011) How can we overcome tumor hypoxia in radiation therapy? J Radiat Res (Tokyo) 52:545–556CrossRef

24.

Maletzki C, Gock M, Klier U, Klar E, Linnebacher M (2010) Bacteriolytic therapy of experimental pancreatic carcinoma. World J Gastroenterol 16:3546–3552PubMedCrossRef

25.

Mott FE, Esana A, Chakmakjian C, Herrington JD (2005) Tumor lysis syndrome in solid tumors. Support Cancer Ther 2:188–191PubMedCrossRef

26.

Pawelek JM, Low KB, Bermudes D (2003) Bacteria as tumour-targeting vectors. Lancet Oncol 4:548–556, ReviewPubMedCrossRef

27.

Zhao M, Geller J, Ma H, Yang M, Penman S, Hoffman RM (2007) Monotherapy with a tumor-targeting mutant of Salmonella typhimurium cures orthotopic metastatic mouse models of human prostate cancer. Proc Natl Acad Sci U S A 104:10170–10174PubMedCrossRef

28.

Crull K, Weiss S (2011) Antibiotic control of tumor-colonizing Salmonella enterica serovar typhimurium. Exp Biol Med (Maywood) Oct 10

29.

Hayashi K, Zhao M, Yamauchi K, Yamamoto N, Tsuchiya H, Tomita K, Hoffman RM (2009) Cancer metastasis directly eradicated by targeted therapy with a modified Salmonella typhimurium. J Cell Biochem 106:992–8PubMedCrossRef

30.

Yam C, Zhao M, Hayashi K, Ma H, Kishimoto H, McElroy M, Bouvet M, Hoffman RM (2010) Monotherapy with a tumor-targeting mutant of S. typhimurium inhibits liver metastasis in a mouse model of pancreatic cancer. J Surg Res 164:248–255PubMedCrossRef

31.

Toso JF, Gill VJ, Hwu P et al (2002) Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol 20:142–152PubMedCrossRef

32.

Medina E, Goldmann O, Rohde M, Lengeling A, Chhatwal GS (2001) Genetic control of susceptibility to group A streptococcal infection in mice. J Infect Dis 184:846–852PubMedCrossRef

33.

Goldmann O, Chhatwal GS, Medina E (2005) Contribution of natural killer cells to the pathogenesis of septic shock induced by Streptococcus pyogenes in mice. J Infect Dis 191:1280–1286PubMedCrossRef

34.

Kreikemeyer B, Klenk M, Podbielski A (2004) The intracellular status of Streptococcus pyogenes: role of extracellular matrix-binding proteins and their regulation. Int J Med Microbiol 294:177–188PubMedCrossRef

35.

Linnebacher M, Maletzki C, Emmrich J, Kreikemeyer B (2008) Lysates of S. pyogenes serotype M49 induce pancreatic tumor growth delay by specific and unspecific antitumor immune responses. J Immunother 31:704–713PubMedCrossRef

36.

Klier U, Maletzki C, Göttmann N, Kreikemeyer B, Linnebacher M (2011) Avitalized bacteria mediate tumor growth control via activation of innate immunity. Cell Immunol 269:120–127PubMedCrossRef

37.

Roca JM, Alonso V, Pericay C et al (2010) ACROSS Cooperative Group. Cetuximab given every 2 weeks plus irinotecan is an active and safe option for previously treated patients with metastatic colorectal cancer. Chemotherapy 56:142–146PubMedCrossRef

38.

Eng C (2010) The evolving role of monoclonal antibodies in colorectal cancer: early presumptions and impact on clinical trial development. Oncologist 15:73–84PubMedCrossRef

39.

Assenat E, Desseigne F, Thezenas S, et al (2011) Cetuximab Plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist. Oct 20

40.

Rosevear HM, Lightfoot AJ, O'Donnell MA, Griffith TS (2009) The role of neutrophils and TNF-related apoptosis-inducing ligand (TRAIL) in bacillus Calmette–Guérin (BCG) immunotherapy for urothelial carcinoma of the bladder. Cancer Metastasis Rev 28:345–353PubMedCrossRef

41.

Azuma I, Seya T (2001) Development of immunoadjuvants for immunotherapy of cancer. Int Immunopharmacol 1:1249–1259PubMedCrossRef

42.

Udagawa M, Kudo-Saito C, Hasegawa G, Yano K, Yamamoto A, Yaguchi M, Toda M, Azuma I, Iwai T, Kawakami Y (2006) Enhancement of immunologic tumor regression by intratumoral administration of dendritic cells in combination with cryoablative tumor pretreatment and Bacillus Calmette–Guerin cell wall skeleton stimulation. Clin Cancer Res 12:7465–7475PubMedCrossRef

43.

Seremet T, Brasseur F, Coulie PG (2011) Tumor-specific antigens and immunologic adjuvants in cancer immunotherapy. Cancer J 17:325–330PubMedCrossRef

44.

Chiang CL, Kandalaft LE, Coukos G (2011) Adjuvants for enhancing the immunogenicity of whole tumor cell vaccines. Int Rev Immunol 30:150–182PubMedCrossRef

45.

Paterson Y, Guirnalda PD, Wood LM (2010) Listeria and Salmonella bacterial vectors of tumor-associated antigens for cancer immunotherapy. Semin Immunol 22:183–189PubMedCrossRef

46.

Xu F, Ulmer JB (2003) Attenuated salmonella and shigella as carriers for DNA vaccines. J Drug Target 11:481–488PubMedCrossRef

47.

Daudel D, Weidinger G, Spreng S (2007) Use of attenuated bacteria as delivery vectors for DNA vaccines. Expert Rev Vaccines 6:97–110PubMedCrossRef

48.

Zhu X, Zhou P, Cai J, Yang G, Liang S, Ren D (2010) Tumor antigen delivered by Salmonella III secretion protein fused with heat shock protein 70 induces protection and eradication against murine melanoma. Cancer Sci 101:2621–2628PubMedCrossRef

49.

Gardlik R, Fruehauf JH (2010) Bacterial vectors and delivery systems in cancer therapy. IDrugs 13:701–706PubMed

50.

Kudela P, Koller VJ, Lubitz W (2010) Bacterial ghosts (BGs)—advanced antigen and drug delivery system. Vaccine 28:5760–5767PubMedCrossRef

51.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRef

52.

Boccardo E, Villa LL (2007) Viral origins of human cancer. Curr Med Chem 14:2526–2539PubMedCrossRef

53.

Suzuki H, Iwasaki E, Hibi T (2009) Helicobacter pylori and gastric cancer. Gastric Cancer 12:79–87PubMedCrossRef

54.

Chemin I, Zoulim F (2009) Hepatitis B virus induced hepatocellular carcinoma. Cancer Lett 286:52–59PubMedCrossRef

55.

Huh WK (2009) Human papillomavirus infection: a concise review of natural history. Obstet Gynecol 114:139–143PubMed

56.

Schmitt M, Dalstein V, Waterboer T, Clavel C, Gissmann L, Pawlita M (2010) Diagnosing cervical cancer and high-grade precursors by HPV16 transcription patterns. Cancer Res 70:249–256PubMedCrossRef

57.

Kwon JH, Choi JY, Jang JW et al (2010) Impact of serial hepatitis B virus DNA on hepatocellular carcinoma development in patients with liver cirrhosis. Intervirology 53:111–118PubMedCrossRef

58.

Sachs G, Scott DR, Wen Y (2011) Gastric infection by Helicobacter pylori. Curr Gastroenterol Rep 14

59.

Chang MH (2009) Cancer prevention by vaccination against hepatitis B. Recent Results Cancer Res 181:85–94PubMedCrossRef

60.

Lu B, Kumar A, Castellsagué X, Giuliano AR (2011) Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review & meta-analysis. BMC Infect Dis 12(11):13CrossRef

61.

Broad A, Kirby JA, Jones DE (2007) Applied Immunology and Transplantation Research Group. Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production. Immunology 120:103–111PubMedCrossRef

62.

Vanden Bush TJ, Bishop GA (2008) TLR7 and CD40 cooperate in IL-6 production via enhanced JNK and AP-1 activation. Eur J Immunol 38:400–409CrossRef

63.

Zhang X, Munegowda MA, Yuan J, Wei Y, Xiang J (2010) Optimal TLR9 signal converts tolerogenic CD4-8- DCs into immunogenic ones capable of stimulating antitumor immunity via activating CD4+ Th1/Th17 and NK cell responses. J Leukoc Biol 88:393–403PubMedCrossRef

64.

Wesch D, Peters C, Oberg HH, Pietschmann K, Kabelitz D (2011) Modulation of γδ T cell responses by TLR ligands. Cell Mol Life Sci 68:2357–2370PubMedCrossRef

65.

Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, Mayer L, Unkeless JC, Xiong H (2005) Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65:5009–5014PubMedCrossRef

66.

Dalpke AH, Lehner MD, Hartung T, Heeg K (2005) Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance. Immunology 116:203–212PubMedCrossRef

67.

Sheyhidin I, Nabi G, Hasim A, Zhang RP, Ainiwaer J, Ma H, Wang H (2011) Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma. World J Gastroenterol 17:3745–3751PubMedCrossRef

68.

Cherfils-Vicini J, Platonova S, Gillard M et al (2010) Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 120:1285–1297PubMedCrossRef

69.

Khan MN, Lee YS (2011) Cyclooxygenase inhibitors: scope of their use and development in cancer chemotherapy. Med Res Rev 31:161–201PubMedCrossRef

70.

Vinogradova Y, Coupland C, Hippisley-Cox J (2011) Exposure to cyclooxygenase-2 inhibitors and risk of cancer: nested case-control studies. Br J Cancer 105:452–459PubMedCrossRef

71.

Stagg J, Johnstone RW, Smyth MJ (2007) From cancer immunosurveillance to cancer immunotherapy. Immunol Rev 220:82–101PubMedCrossRef

72.

Erreni M, Mantovani A, Allavena P (2011) Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron 4:141–154PubMedCrossRef

73.

Mantovani A, Sica A, Allavena P, Garlanda C, Locati M (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol 70:325–330PubMedCrossRef

74.

Nagaraj S, Gabrilovich DI (2010) Myeloid-derived suppressor cells in human cancer. Cancer J 16:348–353PubMedCrossRef

75.

Porta C, Subra Kumar B, Larghi P, Rubino L, Mancino A, Sica A (2007) Tumor promotion by tumor-associated macrophages. Adv Exp Med Biol 604:67–86PubMedCrossRef

76.

Porta C, Riboldi E, Totaro MG, Strauss L, Sica A, Mantovani A (2011) Macrophages in cancer and infectious diseases: the 'good' and the 'bad'. Immunotherapy 3:1185–1202PubMedCrossRef

77.

Mantovani A, Germano G, Marchesi F, Locatelli M, Biswas SK (2011) Cancer-promoting tumor-associated macrophages: new vistas and open questions. Eur J Immunol 41:2522–2525PubMedCrossRef

78.

Watkins SK, Li B, Richardson KS, Head K, Egilmez NK, Zeng Q, Suttles J, Stout RD (2009) Rapid release of cytoplasmic IL-15 from tumor-associated macrophages is an initial and critical event in IL-12-initiated tumor regression. Eur J Immunol 39:2126–2135PubMedCrossRef

79.

Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich D (2011) Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest 121:4015–4029PubMedCrossRef

80.

Ladoire S, Martin F, Ghiringhelli F (2011) Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother 60:909–918PubMedCrossRef

81.

Wilke CM, Kryczek I, Wei S, Zhao E, Wu K, Wang G, Zou W (2011) Th17 cells in cancer: help or hindrance? Carcinogenesis 32:643–649PubMedCrossRef

Title: Bacterial immunotherapy of gastrointestinal tumors
Authors: Michael Linnebacher
Claudia Maletzki
Ulrike Klier
Ernst Klar
Publication date: 01-04-2012
Publisher: Springer-Verlag
Published in: Langenbeck's Archives of Surgery / Issue 4/2012
Print ISSN: 1435-2443
Electronic ISSN: 1435-2451
DOI: https://doi.org/10.1007/s00423-011-0892-6

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Bacterial immunotherapy of gastrointestinal tumors

Abstract

Background

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Results

Conclusion

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