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Cited by 33HER2/EGFR in Cancer ResearchImmunotherapy and Immune ResponsesMonoclonal and Polyclonal Antibodies Research

HER2-Displaying M13 Bacteriophages induce Therapeutic Immunity against Breast Cancer

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Wang, Junbiao, Lamolinara, Alessia, Conti, Laura, Giangrossi, Mara, Cui, Lishan, Morelli, Maria Beatrice, Amantini, Consuelo, Falconi, Maurizio +14 more·2022·Cancers
DOI 10.3390/cancers14164054PMC PMC9406369
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Abstract

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient’s immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment.

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  • M13 filamentous phages displaying HER2/neu epitopes elicited antigen-specific cytotoxic T lymphocyte responses and suppressed tumor growth in murine breast cancer models.

    “For example, M13 filamentous phages displaying HER2/neu epitopes elicited antigen-specific cytotoxic T lymphocyte responses and suppressed tumor growth in murine breast cancer models [80,81]”

    From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [81]

    Results §3.1 reports reduced mammary tumor growth in vaccinated Δ16HER2 mice and T-cell cytotoxicity after Δ16ECTM-phage vaccination, tested against a HER2-positive breast cancer cell line. Methods §2.10 describes a cytotoxicity assay using unfractionated splenocytes; our copy does not establish that the responding cells were cytotoxic T lymphocytes or that their response was antigen-specific. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Engineered phage vaccines displaying tumor-associated antigens or delivering immunostimulatory cargo have demonstrated robust antitumor immunity and survival benefits in multiple mouse models.

    “In parallel, engineered phage vaccines displaying tumor-associated antigens or delivering immunostimulatory cargo have demonstrated robust antitumor immunity and survival benefits in multiple mouse models [80–85]”

    From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [81]

    The Results (§3.1; page unavailable) show that HER2-displaying phage vaccines induced anti-HER2 antibodies and delayed tumor onset while reducing tumor growth in Δ16HER2 mice. The paper does not report a survival benefit or test delivery of immunostimulatory cargo; its own experiments use one breast-cancer mouse model. The Introduction (§1; page unavailable) discusses evidence from other tumor models, but that does not establish the claimed survival benefit. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Together, these studies identify well-defined candidates for first-in-human evaluation.

    “Together, these studies identify well-defined candidates for first-in-human evaluation while underscoring the need to address translational barriers related to scalability, regulatory approval, and patient stratification.”

    From Phage therapy in oncology: opportunities for cancer prevention and treatment (2026) · cites this paper as [81]

    The Introduction (page unavailable) identifies specific HER2-displaying phage vaccines and calls anti-HER2 phage vaccination a possible future option for patients. The Discussion (page unavailable) reports therapeutic effects in a preclinical mouse model. These passages support identifying promising candidates, but they do not establish that the vaccines are ready for first-in-human evaluation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 46

  1. [1]Yakes F.M. Chinratanalab W. Ritter C.A. King W. Seelig S. Arteaga C.L. Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action Cancer Res. 2002 62 4132 4141 12124352
  2. [2]Maadi H. Soheilifar M.H. Choi W.S. Moshtaghian A. Wang Z. Trastuzumab Mechanism of Action. 20 Years of Research to Unravel a Dilemma Cancers 2021 13 3540 10.3390/cancers13143540 34298754 PMC8303665 · DOI
  3. [3]Vu T. Claret F.X. Trastuzumab: Updated mechanisms of action and resistance in breast cancer Front Oncol. 2012 2 62 67 10.3389/fonc.2012.00062 22720269 PMC3376449 · DOI
  4. [4]Scott A.M. Wolchok J.D. Old L.J. Antibody therapy of cancer Nat Rev Cancer. 2012 12 278 287 10.1038/nrc3236 22437872 · DOI
  5. [5]De Melo Gagliato D. Jardim D.L. Marchesi M.S. Hortobagyi G.N. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer Oncotarget 2016 7 64431 64446 10.18632/oncotarget.7043 26824988 PMC5325455 · DOI
  6. [6]Dall P. Lenzen G. Göhler T. Lerchenmüller C. Feisel-Schwickardi G. Koch T. Eggert J. Heilmann V. Schindler C. Wilke J. Trastuzumab in the treatment of elderly patients with early breast cancer: Results from an observational study in Germany J. Geriatr. Oncol. 2015 6 462 469 10.1016/j.jgo.2015.06.003 26341962 · DOI
  7. [7]Quaglino E. Mastini C. Amici A. Marchini C. Iezzi M. Lanzardo S. De Giovanni C. Montani M. Lollini P.L. Masucci G. A better immune reaction to Erbb-2 tumors is elicited in mice by DNA vaccines encoding rat/human chimeric proteins Cancer Res. 2010 70 2604 2612 10.1158/0008-5472.CAN-09-2548 20332241 · DOI
  8. [8]Marchini C. Kalogris C. Garulli C. Pietrella L. Gabrielli F. Curcio C. Quaglino E. Cavallo F. Amici A. Tailoring DNA Vaccines: Designing Strategies against HER2-Positive Cancers Front. Oncol. 2013 3 122 127 10.3389/fonc.2013.00122 23675574 PMC3653119 · DOI
  9. [9]Solinas C. Aiello M. Migliori E. Willard-Gallo K. Emens L.A. Breast cancer vaccines: Heeding the lessons of the past to guide a path forward Cancer Treat. Rev. 2020 84 101947 101964 10.1016/j.ctrv.2019.101947 31926403 · DOI
  10. [10]Arab A. Yazdian-Robati R. Behravan J. HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development Arch. Immunol. Ther. Exp. 2020 68 2 19 10.1007/s00005-019-00566-1 PMC7223380 31915932 · DOI
  11. [11]Aghebati-Maleki L. Bakhshinejad B. Baradaran B. Motallebnezhad M. Aghebati-Maleki A. Nickho H. Yousefi M. Majidi J. Phage display as a promising approach for vaccine development J. Biomed. Sci. 2016 23 66 83 10.1186/s12929-016-0285-9 27680328 PMC5041315 · DOI
  12. [12]Sioud M. Phage Display Libraries: From Binders to Targeted Drug Delivery and Human Therapeutics Mol. Biotechnol. 2019 61 286 303 10.1007/s12033-019-00156-8 30729435 · DOI
  13. [13]Hess K.L. Jewell C.M. Phage display as a tool for vaccine and immunotherapy development Bioeng. Transl. Med. 2019 5 e10142 e10156 10.1002/btm2.10142 31989033 PMC6971447 · DOI · Paper page
  14. [14]Sartorius R. D’Apice L. Barba P. Cipria D. Grauso L. Cutignano A. De Berardinis P. Vectorized Delivery of Alpha-GalactosylCeramide and Tumor Antigen on Filamentous Bacteriophage fd Induces Protective Immunity by Enhancing Tumor-Specific T Cell Response Front. Immunol. 2018 9 1496 1508 10.3389/fimmu.2018.01496 30002659 PMC6031736 · DOI
  15. [15]Gaubin M. Fanutti C. Mishal Z. Durrbach A. De Berardinis P. Sartorius R. Del Pozzo G. Guardiola J. Perham R.N. Piatier-Tonneau D. Processing of filamentous bacteriophage virions in antigen-presenting cells targets both HLA class I and class II peptide loading compartments DNA Cell Biol. 2003 22 11 18 10.1089/104454903321112451 12590733 · DOI
  16. [16]Sartorius R. Pisu P. D’Apice L. Pizzella L. Romano C. Cortese G. Giorgini A. Santoni A. Velotti F. De Berardinis P. The use of filamentous bacteriophage fd to deliver MAGE-A10 or MAGE-A3 HLA-A2-restricted peptides and to induce strong antitumor CTL responses J. Immunol. 2008 180 3719 3728 10.4049/jimmunol.180.6.3719 18322177 · DOI
  17. [17]Fang J. Wang G. Yang Q. Song J. Wang Y. Wang L. The potential of phage display virions expressing malignant tumor specific antigen MAGE-A1 epitope in murine model Vaccine 2005 23 4860 4866 10.1016/j.vaccine.2005.05.024 16029917 · DOI
  18. [18]Asadi-Ghalehni M. Rasaee M.J. Namvar Asl N. Khosravani M. Rajabibazl M. Khalili S. Modjtahedi H. Sadroddiny E. Construction of a Recombinant Phage-vaccine Capable of Reducing the Growth Rate of an Established LL2 Tumor Model Iran. J. Allergy Asthma Immunol. 2018 17 240 249 29908541
  19. [19]Arab A. Nicastro J. Slavcev R. Razazan A. Barati N. Nikpoor A.R. Brojeni A.A.M. Mosaffa F. Badiee A. Jaafari M.R. Lambda phage nanoparticles displaying HER2-derived E75 peptide induce effective E75-CD8+ T response Immunol. Res. 2018 66 200 206 10.1007/s12026-017-8969-0 29143917 · DOI
  20. [20]Razazan A. Nicastro J. Slavcev R. Barati N. Arab A. Mosaffa F. Jaafari M.R. Behravan J. Lambda bacteriophage nanoparticles displaying GP2, a HER2/neu derived peptide, induce prophylactic and therapeutic activities against TUBO tumor model in mice Sci. Rep. 2019 9 2221 2231 10.1038/s41598-018-38371-z 30778090 PMC6379380 · DOI
  21. [21]Roehnisch T. Then C. Nagel W. Blumenthal C. Braciak T. Donzeau M. Böhm T. Bourquin C. Oduncu F. Chemically linked phage idiotype vaccination in the murine B cell lymphoma 1 model J. Transl. Med. 2013 11 267 273 10.1186/1479-5876-11-267 24152874 PMC3819179 · DOI
  22. [22]Roehnisch T. Then C. Nagel W. Blumenthal C. Braciak T. Donzeau M. Böhm T. Flaig M. Bourquin C. Oduncu F.S. Phage idiotype vaccination: First phase I/II clinical trial in patients with multiple myeloma J. Transl. Med. 2014 12 119 129 10.1186/1479-5876-12-119 24885819 PMC4113220 · DOI
  23. [23]Bartolacci C. Andreani C. Curcio C. Occhipinti S. Massaccesi L. Giovarelli M. Galeazzi R. Iezzi M. Tilio M. Gambini V. Phage-Based Anti-HER2 Vaccination Can Circumvent Immune Tolerance against Breast Cancer Cancer Immunol. Res. 2018 6 1486 1498 10.1158/2326-6066.CIR-18-0179 30327365 · DOI · Paper page
  24. [24]Mitra D. Brumlik M.J. Okamgba S.U. Zhu Y. Duplessis T.T. Parvani J.G. Lesko S.M. Brogi E. Jones F.E. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance Mol. Cancer Ther. 2009 8 2152 2162 10.1158/1535-7163.MCT-09-0295 19671734 · DOI · Paper page
  25. [25]Alajati A. Sausgruber N. Aceto N. Duss S. Sarret S. Voshol H. Bonenfant D. Bentires-Alj M. Mammary tumor formation and metastasis evoked by a HER2 splice variant Cancer Res. 2013 73 5320 5327 10.1158/0008-5472.CAN-12-3186 23867476 · DOI
  26. [26]Marchini C. Gabrielli F. Iezzi M. Zenobi S. Montani M. Pietrella L. Kalogris C. Rossini A. Ciravolo V. Castagnoli L. The human splice variant Δ16HER2 induces rapid tumor onset in a reporter transgenic mouse PLoS ONE. 2011 6 e18727 e18733 10.1371/journal.pone.0018727 21559085 PMC3084693 · DOI
  27. [27]Andreani C. Bartolacci C. Wijnant K. Crinelli R. Bianchi M. Magnani M. Hysi A. Iezzi M. Amici A. Marchini C. Resveratrol fuels HER2 and ERα-positive breast cancer behaving as proteasome inhibitor Aging 2017 9 508 523 10.18632/aging.101175 28238967 PMC5361678 · DOI
  28. [28]Segatto I. Zompit M.M. Citron F. D’Andrea S. Vinciguerra G.L.R. Perin T. Berton S. Mungo G. Schiappacassi M. Marchini C. Stathmin Is Required for Normal Mouse Mammary Gland Development and Δ16HER2-Driven Tumorigenesis Cancer Res. 2019 79 397 409 10.1158/0008-5472.CAN-18-2488 30478213 · DOI
  29. [29]Tilio M. Gambini V. Wang J. Garulli C. Kalogris C. Andreani C. Bartolacci C. Elexpuru Zabaleta M. Pietrella L. Hysi A. Irreversible inhibition of Δ16HER2 is necessary to suppress Δ16HER2-positive breast carcinomas resistant to Lapatinib Cancer Lett. 2016 381 76 84 10.1016/j.canlet.2016.07.028 27475932 · DOI
  30. [30]Zazo S. González-Alonso P. Martín-Aparicio E. Chamizo C. Cristóbal I. Arpí O. Rovira A. Albanell J. Eroles P. Lluch A. Generation, characterization, and maintenance of trastuzumab-resistant HER2+ breast cancer cell lines Am. J. Cancer Res. 2016 6 2661 2678 27904779 PMC5126281
  31. [31]Conti L. Bolli E. Di Lorenzo A. Franceschi V. Macchi F. Riccardo F. Ruiu R. Russo L. Quaglino E. Donofrio G. Immunotargeting of the xCT Cystine/Glutamate Antiporter Potentiates the Efficacy of HER2-Targeted Immunotherapies in Breast Cancer Cancer Immunol. Res. 2020 8 1039 1053 10.1158/2326-6066.CIR-20-0082 32532810 · DOI
  32. [32]Palladini A. Nicoletti G. Lamolinara A. Dall’Ora M. Balboni T. Ianzano M.L. Laranga R. Landuzzi L. Giusti V. Ceccarelli C. HER2 isoforms co-expression differently tunes mammary tumor phenotypes affecting onset, vasculature and therapeutic response Oncotarget 2017 8 54444 54458 10.18632/oncotarget.17088 28903354 PMC5589593 · DOI
  33. [33]Giacinti C. Giordano A. RB and cell cycle progression Oncogene 2006 25 5220 5227 10.1038/sj.onc.1209615 16936740 · DOI
  34. [34]Hunter T. Pines J. Cyclins and cancer. II: Cyclin D and CDK inhibitors come of age Cell 1994 79 573 582 10.1016/0092-8674(94)90543-6 7954824 · DOI
  35. [35]Fiszman G.L. Jasnis M.A. Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer Int. J. Breast Cancer 2011 2011 352182 352192 10.4061/2011/352182 22295219 PMC3262573 · DOI
  36. [36]Dafni U. Martín-Lluesma S. Balint K. Tsourti Z. Vervita K. Chenal J. Coukos G. Zaman K. Sarivalasis A. Kandalaft L.E. Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: A 20-year systematic review and meta-analysis Eur. J. Cancer 2021 142 63 82 10.1016/j.ejca.2020.10.014 33221598 · DOI
  37. [37]Corti C. Giachetti P.P.M.B. Eggermont A.M.M. Delaloge S. Curigliano G. Therapeutic vaccines for breast cancer: Has the time finally come? Eur. J. Cancer 2022 160 150 174 10.1016/j.ejca.2021.10.027 34823982 PMC8608270 · DOI
  38. [38]Liu J. Fu M. Wang M. Wan D. Wei Y. Wei X. Cancer vaccines as promising immuno-therapeutics: Platforms and current progress J. Hematol. Oncol. 2022 15 28 53 10.1186/s13045-022-01247-x 35303904 PMC8931585 · DOI
  39. [39]Sartorius R. D’Apice L. Prisco A. De Berardinis P. Arming Filamentous Bacteriophage, a Nature-Made Nanoparticle, for New Vaccine and Immunotherapeutic Strategies Pharmaceutics 2019 11 437 10.3390/pharmaceutics11090437 PMC6781307 31480551 · DOI
  40. [40]Zahavi D. Weiner L. Monoclonal Antibodies in Cancer Therapy Antibodies 2020 9 34 10.3390/antib9030034 PMC7551545 32698317 · DOI
  41. [41]He W. Tan G.S. Mullarkey C.E. Lee A.J. Lam M.M. Krammer F. Henry C. Wilson P.C. Ashkar A.A. Palese P. Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus Proc. Natl. Acad. Sci. USA 2016 113 11931 11936 10.1073/pnas.1609316113 27698132 PMC5081650 · DOI
  42. [42]Montgomery R.B. Makary E. Schiffman K. Goodell V. Disis M.L. Endogenous anti-HER2 antibodies block HER2 phosphorylation and signaling through extracellular signal-regulated kinase Cancer Res. 2005 65 650 656 10.1158/0008-5472.650.65.2 15695410 · DOI
  43. [43]Smith A.E. Ferraro E. Safonov A. Morales C.B. Lahuerta E.J.A. Li Q. Kulick A. Ross D. Solit D.B. de Stanchina E. HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway Nat. Commun. 2021 12 6667 6676 10.1038/s41467-021-27093-y 34795269 PMC8602441 · DOI
  44. [44]Ren X.R. Wei J. Lei G. Wang J. Lu J. Xia W. Spector N. Barak L.S. Clay T.M. Osada T. Polyclonal HER2-specific antibodies induced by vaccination mediate receptor internalization and degradation in tumor cells Breast Cancer Res. 2012 14 R89 R106 10.1186/bcr3204 22676470 PMC3446352 · DOI
  45. [45]Turpin J. Ling C. Crosby E.J. Hartman Z.C. Simond A.M. Chodosh L.A. Rennhack J.P. Andrechek E.R. Ozcelik J. Hallett M. The ErbB2ΔEx16 splice variant is a major oncogenic driver in breast cancer that promotes a pro-metastatic tumor microenvironment Oncogene 2016 35 6053 6064 10.1038/onc.2016.129 27157621 PMC5102823 · DOI
  46. [46]Gu S. Hu Z. Ngamcherdtrakul W. Castro D.J. Morry J. Reda M.M. Gray J.W. Yantasee W. Therapeutic siRNA for drug-resistant HER2-positive breast cancer Oncotarget 2016 7 14727 14741 10.18632/oncotarget.7409 26894975 PMC4924747 · DOI

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Authors
Wang, J., Lamolinara, A., Conti, L., Giangrossi, M., Cui, L., Morelli, M. B., Amantini, C., Falconi, M., Bartolacci, C., Andreani, C., Orlando, F., Provinciali, M., Del Pizzo, F. D., Russo, F., Belletti, B., Riccardo, F., Bolli, E., Quaglino, E., Cavallo, F., Amici, A., Iezzi, M., & Marchini, C.
Affiliations
  • Università di Camerino (IT)
  • University of Chieti-Pescara (IT)
  • University of Turin (IT)
  • Istituto Nazionale di Riposo e Cura per Anziani (IT)
  • Center for Advanced Studies and Technology, Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66013 Chieti, Italy
  • University of Trieste (IT)
  • Centro di Riferimento Oncologico (IT)
Corresponding author
  • Iezzi, Manuela
  • Marchini, Cristina
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2022-08-22
Volume
14
Issue
16
Pages
4054
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers14164054
PMC
PMC9406369
OpenAlex
W4292693925
Cited by
33
References
0
Citations by year
2026: 6 · 2025: 9 · 2024: 10 · 2023: 7 · 2022: 1
FWCI
2.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Unicam Scientific Publications (University of Camerino) (submittedVersion, cc-by)
Funders
  • Ministero della Salute
  • Fondazione Umberto Veronesi
  • Università degli Studi di Camerino
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Keywords
HER2-positive breast cancer, M13 bacteriophage, phage display, cancer vaccines, therapeutic vaccination, trastuzumab resistance, anti-HER2 antibody, transgenic mice, ERK1/2 phosphorylation, retinoblastoma protein, BT474 cells

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