Skip to main content

Swords to Ploughshares and Back: The Continuing Threat of Immunomodulatory Research and Development

  • Chapter
  • First Online:
Defense Against Biological Attacks

Abstract

The immune system plays a vital role in many diseases. Motivated by the desire for better treatments, there are ongoing significant efforts aimed at controlling the immune system to improve human health. As the immune system is important in curing, preventing, or causing disease, technological or scientific advances in our understanding or control of the immune system have the potential for misuse. Indeed, the Soviet biological weapons program extensively exploited scientific understanding of the immune system in attempts to use immunomodulatory technologies to enhance or even create biological weapons. In spirit and in practice, today’s research and development are different: the intent and use have, thus far, been exclusively to improve human health. Beneath the well-intended spirit and practice is the reality that today’s research efforts are inalienably linked to the weapons of the past and potentially to those of the future. What benefit or harm can be derived from understanding and control of the immune system is in the eye of the beholder. This chapter explores the research and technologies currently underway, their actual or potential abuses, the broader scope of risks, and approaches to mitigate these risks.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol. 2011;12:509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Becher B, Spath S, Goverman J. Cytokine networks in neuroinflammation. Nat Rev Immunol. 2017;17:49–59. https://doi.org/10.1038/nri.2016.123.

    Article  CAS  PubMed  Google Scholar 

  3. Brownlie RJ, Zamoyska R. T cell receptor signalling networks: branched, diversified and bounded. Nat Rev Immunol. 2013;13:257–69. https://doi.org/10.1038/nri3403.

    Article  CAS  PubMed  Google Scholar 

  4. Worbs T, Hammerschmidt SI, Forster R. Dendritic cell migration in health and disease. Nat Rev Immunol. 2017;17:30–48. https://doi.org/10.1038/nri.2016.116.

    Article  CAS  PubMed  Google Scholar 

  5. Hunig T. The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. Nat Rev Immunol. 2012;12:317–8. https://doi.org/10.1038/nri3192.

    Article  CAS  PubMed  Google Scholar 

  6. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388:2023–38. https://doi.org/10.1016/s0140-6736(16)30173-8.

    Article  CAS  PubMed  Google Scholar 

  7. Weaver SC, Ferro C, Barrera R, Boshell J, Navarro JC. Venezuelan equine encephalitis. Annu Rev Entomol. 2004;49:141–74. https://doi.org/10.1146/annurev.ento.49.061802.123422.

    Article  CAS  PubMed  Google Scholar 

  8. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36:265–76. https://doi.org/10.1016/j.it.2015.02.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Touzot F, Hacein-Bey-Abina S, Fischer A, Cavazzana M. Gene therapy for inherited immunodeficiency. Expert Opin Biol Ther. 2014;14:789–98. https://doi.org/10.1517/14712598.2014.895811.

    Article  CAS  PubMed  Google Scholar 

  10. Vinay DS, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–98. https://doi.org/10.1016/j.semcancer.2015.03.004.

    Article  CAS  PubMed  Google Scholar 

  11. Zaiss AK, Muruve DA. Immunity to adeno-associated virus vectors in animals and humans: a continued challenge. Gene Ther. 2008;15:808–16. https://doi.org/10.1038/gt.2008.54.

    Article  CAS  PubMed  Google Scholar 

  12. Singh P, Pal SA, Alex A, Agarwal N. Development of PROSTVAC immunotherapy in prostate cancer. Future Oncol. 2015;11:2137–48.

    Article  CAS  PubMed  Google Scholar 

  13. Franz DR, Parrott CD, Takafuj ET. The U.S. biological warfare and biological defense programs. In: Medical aspects of chemical and biological warfare. Washington, DC: TMM Publications; 1997. p. 425–36.

    Google Scholar 

  14. Leitenberg M, Zilinskas RA, Kuhn JH. The Soviet biological weapons program. Cambridge: Harvard University Press; 2012.

    Book  Google Scholar 

  15. Stepanov AV, Marinin LI, Pomerantsev AP, Staritsin NA. Development of novel vaccines against anthrax in man. J Biotechnol. 1996;44:155–60. https://doi.org/10.1016/0168-1656(95)00092-5.

    Article  CAS  PubMed  Google Scholar 

  16. Flyak AI, et al. Mechanism of human antibody-mediated neutralization of Marburg virus. Cell. 2015;160:893–903. https://doi.org/10.1016/j.cell.2015.01.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Iannello A, Ahmad A. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev. 2005;24:487–99. https://doi.org/10.1007/s10555-005-6192-2.

    Article  CAS  PubMed  Google Scholar 

  18. Meyer S, Leusen JH, Boross P. Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer. MAbs. 2014;6:1133–44. https://doi.org/10.4161/mabs.29670.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Williams SC. The other microbiome. Proc Natl Acad Sci U S A. 2013;110:2682–4. https://doi.org/10.1073/pnas.1300923110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wylie KM, Weinstock GM, Storch GA. Emerging view of the human virome. Transl Res. 2012;160:283–90. https://doi.org/10.1016/j.trsl.2012.03.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cooper NR, Nemerow GR. The role of antibody and complement in the control of viral infections. J Investig Dermatol. 1984;83:S121–7. https://doi.org/10.1038/jid.1984.33.

    Article  Google Scholar 

  22. Parenti G, Andria G, Ballabio A. Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med. 2015;66:471–86. https://doi.org/10.1146/annurev-med-122313-085916.

    Article  CAS  PubMed  Google Scholar 

  23. Kaufmann KB, Buning H, Galy A, Schambach A, Grez M. Gene therapy on the move. EMBO Mol Med. 2013;5:1642–61. https://doi.org/10.1002/emmm.201202287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Athanasopoulos T, Munye MM, Yanez-Munoz RJ. Nonintegrating gene therapy vectors. Hematol Oncol Clin North Am. 2017;31:753–70. https://doi.org/10.1016/j.hoc.2017.06.007.

    Article  PubMed  Google Scholar 

  25. Lasaro MO, Ertl HC. New insights on adenovirus as vaccine vectors. Mol Ther. 2009;17:1333–9. https://doi.org/10.1038/mt.2009.130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu TC, Thorne SH, Kirn DH. Oncolytic adenoviruses for cancer gene therapy. Methods Mol Biol. 2008;433:243–58.

    Article  CAS  PubMed  Google Scholar 

  27. Dias JD, et al. Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4. Gene Ther. 2012;19:988–98. https://doi.org/10.1038/gt.2011.176.

    Article  CAS  PubMed  Google Scholar 

  28. Sofer-Podesta C, Ang J, Hackett NR, Senina S, Perlin D, Crystal RG, Boyer JL. Adenovirus-mediated delivery of an anti-V antigen monoclonal antibody protects mice against a lethal Yersinia pestis challenge. Infect Immun. 2009;77:1561–8. https://doi.org/10.1128/IAI.00856-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qiu Q, Xu Z, Tian J, Moitra R, Gunti S, Notkins AL, Byrnes AP. Impact of natural IgM concentration on gene therapy with adenovirus type 5 vectors. J Virol. 2015;89:3412–6. https://doi.org/10.1128/JVI.03217-14.

    Article  CAS  PubMed  Google Scholar 

  30. Zak DE, et al. Merck Ad5/HIV induces broad innate immune activation that predicts CD8(+) T-cell responses but is attenuated by preexisting Ad5 immunity. Proc Natl Acad Sci U S A. 2012;109:E3503–12. https://doi.org/10.1073/pnas.1208972109.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Milligan ID, et al. Safety and immunogenicity of novel adenovirus type 26- and modified vaccinia Ankara-aectored Ebola vaccines: a randomized clinical trial. JAMA. 2016;315:1610–23. https://doi.org/10.1001/jama.2016.4218.

    Article  CAS  PubMed  Google Scholar 

  32. Croyle MA, et al. PEGylation of a vesicular stomatitis virus G pseudotyped lentivirus vector prevents inactivation in serum. J Virol. 2004;78:912–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Heider S, Kleinberger S, Kochan F, Dangerfield JA, Metzner C. Immune protection of retroviral vectors upon molecular painting with the complement regulatory protein CD59. Mol Biotechnol. 2016;58:480–8. https://doi.org/10.1007/s12033-016-9944-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stanley DA, et al. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat Med. 2014;20:1126–9. https://doi.org/10.1038/nm.3702.

    Article  CAS  PubMed  Google Scholar 

  35. Cattaneo R, Miest T, Shashkova EV, Barry MA. Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded. Nat Rev Microbiol. 2008;6:529–40. https://doi.org/10.1038/nrmicro1927.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Choi JW, Lee YS, Yun CO, Kim SW. Polymeric oncolytic adenovirus for cancer gene therapy. J Control Release. 2015;219:181–91. https://doi.org/10.1016/j.jconrel.2015.10.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zeng Q, Han J, Zhao D, Gong T, Zhang Z, Sun X. Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus. Int J Nanomedicine. 2012;7:985–97. https://doi.org/10.2147/ijn.S27526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Doronin K, Shashkova EV, May SM, Hofherr SE, Barry MA. Chemical modification with high molecular weight polyethylene glycol reduces transduction of hepatocytes and increases efficacy of intravenously delivered oncolytic adenovirus. Hum Gene Ther. 2009;20:975–88. https://doi.org/10.1089/hum.2009.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Coughlan L, Alba R, Parker AL, Bradshaw AC, McNeish IA, Nicklin SA, Baker AH. Tropism-modification strategies for targeted gene delivery using adenoviral vectors. Viruses. 2010;2:2290–355. https://doi.org/10.3390/v2102290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rojas LA, Condezo GN, Moreno R, Fajardo CA, Arias-Badia M, San Martin C, Alemany R. Albumin-binding adenoviruses circumvent pre-existing neutralizing antibodies upon systemic delivery. J Control Release. 2016;237:78–88. https://doi.org/10.1016/j.jconrel.2016.07.004.

    Article  CAS  PubMed  Google Scholar 

  41. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalation anthrax. J Infect Dis. 1993;167:1239–43.

    Article  CAS  PubMed  Google Scholar 

  42. Sabhnani L, Manocha M, Tomar D, Shashikiran D, Rao DN. Yersinia pestis F1 antigen: a correlation between antibody titres and subclass distribution with differential avidity in different inbred mouse strains. Int Immunopharmacol. 2003;3:1413–8. https://doi.org/10.1016/s1567-5769(03)00138-3.

    Article  CAS  PubMed  Google Scholar 

  43. Skyberg JA. Immunotherapy for tularemia. Virulence. 2013;4:859–70. https://doi.org/10.4161/viru.25454.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Price JL, Manetz TS, Shearer JD, House RV. Preclinical safety assessment of a recombinant plague vaccine (rF1V). Int J Toxicol. 2013;32:327–35. https://doi.org/10.1177/1091581813497405.

    Article  CAS  PubMed  Google Scholar 

  45. Adekar SP, et al. Neutralization of botulinum neurotoxin by a human monoclonal antibody specific for the catalytic light chain. PLoS One. 2008;3:e3023. https://doi.org/10.1371/journal.pone.0003023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen Z, Moayeri M, Purcell R. Monoclonal antibody therapies against anthrax. Toxins (Basel). 2011;3:1004–19. https://doi.org/10.3390/toxins3081004.

    Article  CAS  Google Scholar 

  47. Qiu X, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514:47–53. https://doi.org/10.1038/nature13777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Froude JW, Stiles B, Pelat T, Thullier P. Antibodies for biodefense. MAbs. 2011;3:517–27. https://doi.org/10.4161/mabs.3.6.17621.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Marston HD, Paules CI, Fauci AS. Monoclonal antibodies for emerging infectious diseases – borrowing from history. N Engl J Med. 2018;378:1469–72. https://doi.org/10.1056/NEJMp1802256.

    Article  CAS  PubMed  Google Scholar 

  50. Wheelis M. Biological warfare at the 1346 siege of Caffa. Emerg Infect Dis. 2002;8:971–5.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Du Y. Role of Fraction 1 antigen of Yersinia pestis in Inhibition of phagocytosis. Infect Immun. 2002;70:1453–60. https://doi.org/10.1128/iai.70.3.1453-1460.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sha J, et al. Characterization of an F1 deletion mutant of Yersinia pestis CO92, pathogenic role of F1 antigen in bubonic and pneumonic plague, and evaluation of sensitivity and specificity of F1 antigen capture-based dipsticks. J Clin Microbiol. 2011;49:1708–15. https://doi.org/10.1128/JCM.00064-11.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Oyston PC. Francisella tularensis: unravelling the secrets of an intracellular pathogen. J Med Microbiol. 2008;57:921–30. https://doi.org/10.1099/jmm.0.2008/000653-0.

    Article  PubMed  Google Scholar 

  54. Falugi F, Kim HK, Missiakas DM, Schneewind O. Role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus. MBio. 2013;4:e00575–13. https://doi.org/10.1128/mBio.00575-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bottone EJ. Bacillus cereus, a volatile human pathogen. Clin Microbiol Rev. 2010;23:382–98. https://doi.org/10.1128/CMR.00073-09.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ramarao N, Sanchis V. The pore-forming haemolysins of bacillus cereus: a review. Toxins (Basel). 2013;5:1119–39. https://doi.org/10.3390/toxins5061119.

    Article  CAS  Google Scholar 

  57. Marninin LI, Mockov YV, Staritsin NA, Pomerantzev AP. Expression of cereolysine AB genes in Bacillus anthracis vaccine strain ensures protection agains experimental hymolytic anthrax infection. Vaccine. 1997;15:1846–50.

    Article  Google Scholar 

  58. Palmqvist N, Foster T, Tarkowski A, Josefsson E. Protein A is a virulence factor in Staphylococcus aureus arthritis and septic death. Microb Pathog. 2002;33:239–49. https://doi.org/10.1006/mpat.2002.0533.

    Article  CAS  PubMed  Google Scholar 

  59. Bolton GR, Mehta KK. The role of more than 40 years of improvement in protein A chromatography in the growth of the therapeutic antibody industry. Biotechnol Prog. 2016;32:1193–202. https://doi.org/10.1002/btpr.2324.

    Article  CAS  PubMed  Google Scholar 

  60. Goding JW. Use of staphylococcal protein A as an immunological reagent. J Immunol Methods. 1978;20:241–53.

    Article  CAS  PubMed  Google Scholar 

  61. National Cancer Institute. What is cancer? 2015. https://www.cancer.gov/about-cancer/understanding/what-is-cancer. Accessed 20 Sept 2017.

  62. World Health Organization. The top 10 causes of death. 2017. http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed 20 Sept 2017.

  63. National Cancer Institute. Chemotherapy. 2015. https://www.cancer.gov/about-cancer/treatment/types/chemotherapy#1. Accessed 20 Sept 2017.

  64. Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: Past, present and future. Semin Cancer Biol. 2017;52(Pt 1):56–73. https://doi.org/10.1016/j.semcancer.2017.08.010.

    Article  CAS  PubMed  Google Scholar 

  65. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805:105–17. https://doi.org/10.1016/j.bbcan.2009.11.002.

    Article  CAS  PubMed  Google Scholar 

  66. Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30:658–70. https://doi.org/10.1038/nbt.2287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yarchoan M, Johnson BA, Lutz ER, Laheru DA, Jaffee EM. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17:209–22. https://doi.org/10.1038/nrc.2016.154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer. 2016;4:53. https://doi.org/10.1186/s40425-016-0158-5.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Lun X, et al. Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma. Mol Ther. 2010;18:1927–36. https://doi.org/10.1038/mt.2010.183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Aarts WM, Schlom J, Hodge JW. Vector-based vaccine/cytokine combination therapy to enhance induction of immune responses to a self-antigen and antitumor activity. Cancer Res. 2002;62:5770–7.

    CAS  PubMed  Google Scholar 

  71. Madan RA, Bilusic M, Heery C, Schlom J, Gulley JL. Clinical evaluation of TRICOM vector therapeutic cancer vaccines. Semin Oncol. 2012;39:296–304. https://doi.org/10.1053/j.seminoncol.2012.02.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Hawley RJ, Edward EM. Biological weapons – a primer for microbiologists. Annu Rev Microbiol. 2001;55:235–53.

    Article  CAS  PubMed  Google Scholar 

  73. Zacks MA, Paessler S. Encephalitic alphaviruses. Vet Microbiol. 2010;140:281–6. https://doi.org/10.1016/j.vetmic.2009.08.023.

    Article  CAS  PubMed  Google Scholar 

  74. Hoyer KK, Dooms H, Barron L, Abbas AK. Interleukin-2 in the development and control of inflammatory disease. Immunol Rev. 2008;226:19–28.

    Article  CAS  PubMed  Google Scholar 

  75. Jackson RJ, Ramsay AJ, Christensen CD, Beaton S, Hall DF, Ramshaw IA. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. J Virol. 2001;75:1205–10. https://doi.org/10.1128/JVI.75.3.1205-1210.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. MacKenzie D. US develops lethal new viruses. 2003. https://www.newscientist.com/article/dn4318-us-develops-lethal-new-viruses/. Accessed 20 Sept 2017.

  77. Quaranta S, et al. Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation. Clin Immunol. 1999;91:106–16.

    Article  CAS  PubMed  Google Scholar 

  78. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med. 1998;338:1813–21.

    Article  CAS  PubMed  Google Scholar 

  79. Dutsch-Wicherek M, Kazmierczak W. Creation of a suppressive microenvironment by macrophages and cancer-associated fibroblasts. Front Biosci (Landmark Ed). 2013;18:1003–16.

    Article  CAS  Google Scholar 

  80. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6:e1792. https://doi.org/10.1038/cddis.2015.162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Oleinika K, Nibbs RJ, Graham G, Fraser AR. Suppression, subversion and escape: the role of regulatory T cells in cancer progression. Clin Exp Immunol. 2013;171:36–45. https://doi.org/10.1111/j.1365-2249.2012.04657.x.

    Article  CAS  PubMed  Google Scholar 

  82. Draenert R, Seybold U, Grutzner E, Bogner JR. Novel antibiotics: are we still in the pre-post-antibiotic era? Infection. 2015;43:145–51. https://doi.org/10.1007/s15010-015-0749-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Alter G, Sekaly RP. Beyond adjuvants: antagonizing inflammation to enhance vaccine immunity. Vaccine. 2015;33(Suppl 2):B55–9. https://doi.org/10.1016/j.vaccine.2015.03.058.

    Article  CAS  PubMed  Google Scholar 

  84. Calik Basaran N, Ascioglu S. Epidemiology and management of healthcare-associated bloodstream infections in non-neutropenic immunosuppressed patients: a review of the literature. Ther Adv Infect Dis. 2017;4:171–91. https://doi.org/10.1177/2049936117733394.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Weiner LM, Surana R, Wang S. Monoclonal antibodies: versatile platforms for cancer immunotherapy. Nat Rev Immunol. 2010;10:317–27. https://doi.org/10.1038/nri2744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Maury S, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016;375:1044–53. https://doi.org/10.1056/NEJMoa1605085.

    Article  CAS  PubMed  Google Scholar 

  87. Shetty A, et al. Tocilizumab in the treatment of rheumatoid arthritis and beyond. Drug Des Devel Ther. 2014;8:349–64. https://doi.org/10.2147/DDDT.S41437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rudnicka D, et al. Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity. Blood. 2013;121:4694–702. https://doi.org/10.1182/blood-2013-02-482570.

    Article  CAS  PubMed  Google Scholar 

  89. de Lemos LLP, et al. Rituximab for rheumatoid arthrits treatment: a systematic review. Rev Bras Reumatol Engl Ed. 2014;54:220–30. https://doi.org/10.1016/j.rbre.2013.08.003.

    Article  Google Scholar 

  90. Dierickx D, Kentos A, Delannoy A. The role of rituximab in adults with warm antibody autoimmune hemolytic anemia. Blood. 2015;125:3223–9. https://doi.org/10.1182/blood-2015-01-588392.

    Article  CAS  PubMed  Google Scholar 

  91. Maloney DG, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90:2188–95.

    CAS  PubMed  Google Scholar 

  92. Mok CC. Current role of rituximab in systemic lupus erythematosus. Int J Rheum Dis. 2015;18:154–63. https://doi.org/10.1111/1756-185X.12463.

    Article  CAS  PubMed  Google Scholar 

  93. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61. https://doi.org/10.1016/j.immuni.2014.06.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. https://doi.org/10.1038/nrc3239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Adelfinger M, Bessler S, Frentzen A, Cecil A, Langbein-Laugwitz J, Gentschev I, Szalay AA. Preclinical testing oncolytic vaccinia virus strain GLV-5b451 expressing an anti-VEGF single-chain antibody for canine cancer therapy. Viruses. 2015;7:4075–92. https://doi.org/10.3390/v7072811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Suscovich TJ, Alter G. In situ production of therapeutic monoclonal antibodies. Expert Rev Vaccines. 2015;14:205–19. https://doi.org/10.1586/14760584.2015.1001375.

    Article  CAS  PubMed  Google Scholar 

  97. Adachi Y, Yoshio-Hoshino N, Aoki C, Nishimoto N. VEGF targeting in mesotheliomas using an interleukin-6 signal inhibitor based on adenovirus gene delivery. Anticancer Res. 2010;30:1947–52.

    CAS  PubMed  Google Scholar 

  98. Tutykhina IL, et al. Passive immunization with a recombinant adenovirus expressing an HA (H5)-specific single-domain antibody protects mice from lethal influenza infection. Antivir Res. 2013;97:318–28. https://doi.org/10.1016/j.antiviral.2012.12.021.

    Article  CAS  PubMed  Google Scholar 

  99. Tyrsin D, Chuvpilo S, Matskevich A, Nemenov D, Römer PS, Tabares P, Hünig T. From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34:S45–8.

    Google Scholar 

  100. Respaud R, et al. Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6:1347–55. https://doi.org/10.4161/mabs.29938.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Storti C, Le Noci V, Sommariva M, Tagliabue E, Balsari A, Sfondrini L. Aerosol delivery in the treatment of lung cancer. Curr Cancer Drug Targets. 2015;15:604–12.

    Article  CAS  PubMed  Google Scholar 

  102. Mathew M, Verma RS. Humanized immunotoxins: a new generation of immunotoxins for targeted cancer therapy. Cancer Sci. 2009;100:1359–65. https://doi.org/10.1111/j.1349-7006.2009.01192.x.

    Article  CAS  PubMed  Google Scholar 

  103. Roy CJ, et al. Aerosolized adenovirus-vectored vaccine as an alternative vaccine delivery method. Respir Res. 2011;12:153. https://doi.org/10.1186/1465-9921-12-153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. White AD, et al. Evaluation of the safety and immunogenicity of a candidate tuberculosis vaccine, MVA85A, delivered by aerosol to the lungs of macaques. Clin Vaccine Immunol. 2013;20:663–72. https://doi.org/10.1128/cvi.00690-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Melo AL, Soccol VT, Soccol CR. Bacillus thuringiensis: mechanism of action, resistance, and new applications: a review. Crit Rev Biotechnol. 2016;36:317–26. https://doi.org/10.3109/07388551.2014.960793.

    Article  CAS  PubMed  Google Scholar 

  106. Erlendur H, et al. Bacillus anthracis, Bacillus cereus, and Bacillus thuringiensis—one species on the basis of genetic evidence. Appl Environ Microbiol. 2000;66:2627–30.

    Article  Google Scholar 

  107. Hanham M. Kim Jong Un tours pesticide facility capable of producing biological weapons: a 38 North special report. 2015. http://www.38north.org/2015/07/mhanham070915/. Accessed 7 Feb 2018.

  108. Federation of American Scientists. US department of defense news briefing. 2001. https://fas.org/sgp/news/2001/09/dod090401.html. Accessed 25 Sept 2017.

  109. Miller, J, Engelberg, S, Broad, WJ. U.S. germ warfare research pushes treaty limits. 2001.

    Google Scholar 

  110. CDC/USDA. Federal Select Agent Program.

    Google Scholar 

  111. CDC/USDA. Restricted experiments guidance. 2017.

    Google Scholar 

  112. Centers for Disease Control and Prevention, United States Department of Agriculture. Federal select agent program. 2017. https://www.selectagents.gov/. Accessed 3 Oct 2017.

  113. Government US. United States government policy for institutional oversight of life sciences dual use research of concern. 2014. Online.

    Google Scholar 

  114. UNODA. Biological weapons. 2018. https://www.un.org/disarmament/wmd/bio/. Accessed 18 May 2018.

  115. UNODA. Guide to participating in the confidence-building measures of the biological weapons convention. 2015.

    Google Scholar 

  116. Koblentz GD, Chevrier MI. Modernizing confidence-building measures for the biological weapons convention. Biosecur Bioterror. 2011;9:232–8. https://doi.org/10.1089/bsp.2011.0023.

    Article  PubMed  Google Scholar 

  117. Barash JR, Arnon SS. A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins. J Infect Dis. 2014;209:183–91. https://doi.org/10.1093/infdis/jit449.

    Article  CAS  PubMed  Google Scholar 

  118. Dover N, Barash JR, Hill KK, Xie G, Arnon SS. Molecular characterization of a novel botulinum neurotoxin type H gene. J Infect Dis. 2014;209:192–202. https://doi.org/10.1093/infdis/jit450.

    Article  CAS  PubMed  Google Scholar 

  119. Arnon SS, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059–70.

    Article  CAS  PubMed  Google Scholar 

  120. Hooper DC, Hirsch MS. Novel clostridium botulinum toxin and dual use research of concern issues. J Infect Dis. 2014;209:167. https://doi.org/10.1093/infdis/jit528.

    Article  PubMed  Google Scholar 

  121. Keim P. A novel botulinum neurotoxin and how it tested our scientific institutions. J Infect Dis. 2016;213:332–4. https://doi.org/10.1093/infdis/jiv328.

    Article  PubMed  Google Scholar 

  122. Maslanka SE, et al. A novel botulinum neurotoxin, previously reported as serotype H, has a hybrid-like structure with regions of similarity to the structures of serotypes A and F and is neutralized with serotype A antitoxin. J Infect Dis. 2016;213:379–85. https://doi.org/10.1093/infdis/jiv327.

    Article  CAS  PubMed  Google Scholar 

  123. Broad WJ. Gene-engineered anthrax: is it a weapon? The New York Times. 1998.

    Google Scholar 

Download references

Acknowledgments

This work was funded in part through the NIAID Division of Intramural Research. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services (DHHS) or of the institutions and companies affiliated with the authors. Mention of trade names, commercial products, or organizations do not imply endorsement by the U.S. Government.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph P. Cornish .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Cornish, J.P., Johnson, R.F. (2019). Swords to Ploughshares and Back: The Continuing Threat of Immunomodulatory Research and Development. In: Singh, S., Kuhn, J. (eds) Defense Against Biological Attacks. Springer, Cham. https://doi.org/10.1007/978-3-030-03053-7_10

Download citation

Publish with us

Policies and ethics