HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development


Clinical progress in the field of HER2-positive breast cancer therapy has been dramatically improved by understanding of the immune regulatory mechanisms of tumor microenvironment. Passive immunotherapy utilizing recombinant monoclonal antibodies (mAbs), particularly trastuzumab and pertuzumab has proved to be an effective strategy in HER2-positive breast cancer treatment. However, resistance to mAb therapy and relapse of disease are still considered important challenges in clinical practice. There are increasing reports on the induction of cellular and humoral immune responses in HER2-positive breast cancer patients. More recently, increasing efforts are focused on using HER2-derived peptide vaccines for active immunotherapy. Here, we discuss the development of various HER2-derived vaccines tested in animal models and human clinical trials. Different formulations and strategies to improve immunogenicity of the antigens in animal studies are also discussed. Furthermore, other immunotherapeutic approaches to HER2 breast cancer including, CTLA-4 inhibitors, immune checkpoint inhibitors, anti PD-1/PD-L1 antibodies are presented.

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  1. Aboud-Pirak E, Hurwitz E, Pirak ME et al (1988) Efficacy of antibodies to epidermal growth factor receptor against KB carcinoma in vitro and in nude mice. J Natl Cancer Inst 80:1605–1611

  2. Al-Awadhi A, Lee Murray J, Ibrahim NK (2018) Developing anti-HER 2 vaccines: B reast cancer experience. Int J Cancer 143:2126–2132

  3. Alexe G, Dalgin GS, Scanfeld D et al (2007) High expression of lymphocyte-associated genes in node-negative HER2 + breast cancers correlates with lower recurrence rates. Cancer Res 67:10669–10676

  4. Alsaab HO, Sau S, Alzhrani R et al (2017) PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Front Pharmacol 8:561

  5. Alving CR (1991) Liposomes as carriers of antigens and adjuvants. J Immunol Methods 140:1–13

  6. Apostolopoulos V, Pietersz GA, Tsibanis A et al (2006) Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835]. Breast Cancer Res 8:R27

  7. Arab A, Behravan J, Razazan A et al (2018a) A nano-liposome vaccine carrying E75, a HER-2/neu-derived peptide, exhibits significant antitumour activity in mice. J Drug Target 26:365–372

  8. Arab A, Nicastro J, Slavcev R et al (2018b) Lambda phage nanoparticles displaying HER2-derived E75 peptide induce effective E75-CD8 + T response. Immunol Res 66:200–206

  9. Arab A, Robati RY, Nicastro J et al (2018c) Phage-based nanomedicines as new immune therapeutic agents for breast cancer. Curr Pharm Des 24:1195–1203

  10. Arab A, Behravan N, Razazn A et al (2019) The viral approach to breast cancer immunotherapy. J Cell Physiol 234:1257–1267

  11. Arteaga CL, Winnier AR, Poirier MC et al (1994) p185c-erbB-2 signaling enhances cisplatin-induced cytotoxicity in human breast carcinoma cells: association between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. Cancer Res 54:3758–3765

  12. Ayoub NM, Al-Shami KM, Yaghan RJ (2019) Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer 11:53–69

  13. Barati N, Nikpoor AR, Razazan A et al (2017) Nanoliposomes carrying HER2/neu-derived peptide AE36 with CpG-ODN exhibit therapeutic and prophylactic activities in a mice TUBO model of breast cancer. Immunol Lett 190:108–117

  14. Barati N, Razazan A, Nicastro J et al (2018) Immunogenicity and antitumor activity of the superlytic λF7 phage nanoparticles displaying a HER2/neu-derived peptide AE37 in a tumor model of BALB/c mice. Cancer Lett 424:109–116

  15. Batista FD, Harwood NE (2009) The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9:15–27

  16. Behravan J, Razazan A, Behravan G (2018) Towards breast cancer vaccines, progressand challenges. Curr Drug Discov Technol.

  17. Benavides L, Holmes J, Gates J et al (2008) Results of the first phase I clinical trial of the novel Ii-key hybrid preventive HER2/neu peptide (AE37) vaccine: United States Military Cancer Institute Clinical Trials Group Study I-03. J Clin Oncol 26:3016

  18. Bi J, Zhao J, Bao L et al (2008) Preparation and anti-tumor evaluation of polyactin A microparticles from supercritical CO2 processing. Appl Surf Sci 255:320–323

  19. Bozeman EN, He S, Shafizadeh Y et al (2016) Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12. Hum Vaccin Immunother 12:421–430

  20. Brossart P, Stuhler G, Flad T et al (1998) Her-2/neu-derived peptides are tumor-associated antigens expressed by human renal cell and colon carcinoma lines and are recognized by in vitro induced specific cytotoxic T lymphocytes. Cancer Res 58:732–736

  21. Bryson PD, Han X, Truong N et al (2017) Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth. Vaccine 35:5842–5849

  22. Carmichael MG, Benavides LC, Holmes JP et al (2010) Results of the first phase 1 clinical trial of the HER-2/neu peptide (GP2) vaccine in disease-free breast cancer patients: United States Military Cancer Institute Clinical Trials Group Study I-04. Cancer 116:292–301

  23. Chen Y, Hu D, Eling DJ et al (1998) DNA vaccines encoding full-length or truncated Neu induce protective immunity against Neu-expressing mammary tumors. Cancer Res 58:1965–1971

  24. Chen Y, Emtage P, Zhu Q et al (2001) Induction of ErbB-2/neu-specific protective and therapeutic antitumor immunity using genetically modified dendritic cells: enhanced efficacy by cotransduction of gene encoding IL-12. Gene Ther 8:316–323

  25. Chin Y, Janseens J, Vandepitte J et al (1992) Phenotypic analysis of tumor-infiltrating lymphocytes from human breast cancer. Anticancer Res 12:1463–1466

  26. Clifton GT, Gall V, Peoples GE et al (2016) Clinical development of the E75 vaccine in breast cancer. Breast Care 11:116–121

  27. Clifton GT, Peace KM, Holmes JP et al (2019) Initial safety analysis of a randomized phase II trial of nelipepimut-S + GM-CSF and trastuzumab compared to trastuzumab alone to prevent recurrence in breast cancer patients with HER2 low-expressing tumors. Clin Immunol 201:48–54

  28. Clive KS, Tyler JA, Clifton GT et al (2012) The GP2 peptide: a HER2/neu-based breast cancer vaccine. J Surg Oncol 105:452–458

  29. Costa R, Soliman H, Czerniecki B (2017) The clinical development of vaccines for HER2 + breast cancer: current landscape and future perspectives. Cancer Treat Rev 61:107–115

  30. Cruz JSD, Lau SY, Ramirez EM et al (2003) Protein vaccination with the HER2/neu extracellular domain plus anti-HER2/neu antibody–cytokine fusion proteins induces a protective anti-HER2/neu immune response in mice. Vaccine 21:1317–1326

  31. Cui N, Shi J, Yang C (2018) HER2-based immunotherapy for breast cancer. Cancer Biother Radiopharm 33:169–175

  32. Curigliano G, Romieu G, Campone M et al (2016) A phase I/II trial of the safety and clinical activity of a HER2-protein based immunotherapeutic for treating women with HER2-positive metastatic breast cancer. Breast Cancer Res Treat 156:301–310

  33. Czerniecki BJ, Koski GK, Koldovsky U et al (2007) Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res 67:1842–1852

  34. Datta J, Xu S, Rosemblit C et al (2015) CD4+ T-helper type 1 cytokines and trastuzumab facilitate CD8+ T cell targeting of HER2/neu–expressing cancers. Cancer Immunol Res 3:455–463

  35. Datta J, Fracol M, McMillan MT et al (2016) Association of depressed anti-HER2 T-helper type 1 response with recurrence in patients with completely treated HER2-positive breast cancer: role for immune monitoring. JAMA Oncol 2:242–246

  36. De La Cruz LM, Nocera NF, Czerniecki BJ (2016) Restoring anti-oncodriver Th1 responses with dendritic cell vaccines in HER2/neu-positive breast cancer: progress and potential. Immunotherapy 8:1219–1232

  37. Diaz CM, Chiappori A, Aurisicchio L et al (2013) Phase 1 studies of the safety and immunogenicity of electroporated HER2/CEA DNA vaccine followed by adenoviral boost immunization in patients with solid tumors. J Transl Med 11:62

  38. Disis ML, Calenoff E, McLaughlin G et al (1994) Existent T cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res 54:16–20

  39. Disis ML, Grabstein KH, Sleath PR et al (1999) Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin Cancer Res 5:1289–1297

  40. Disis ML, Schiffman K, Guthrie K et al (2004) Effect of dose on immune response in patients vaccinated with an her-2/neu intracellular domain protein-based vaccine. J Clin Oncol 22:1916–1925

  41. Dissanayake D, Murakami K, Tran MD et al (2014) Peptide-pulsed dendritic cells have superior ability to induce immune-mediated tissue destruction compared to peptide with adjuvant. PLoS One 9:e92380

  42. Dollins CM, Nair S, Sullenger BA (2008) Aptamers in immunotherapy. Hum Gene Ther 19:443–450

  43. Doyle HA, Koski RA, Bonafé N et al (2018) Epidermal growth factor receptor peptide vaccination induces cross-reactive immunity to human EGFR, HER2, and HER3. Cancer Immunol Immunother 67:1559–1569

  44. Eager R, Nemunaitis J (2011) Clinical development directions in oncolytic viral therapy. Cancer Gene Ther 18:305–317

  45. Elahian F, Kalalinia F, Behravan J (2009) Dexamethasone downregulates BCRP mRNA and protein expression in breast cancer cell lines. Oncol Res 18(1):9–15

  46. Emens LA, Asquith JM, Leatherman JM et al (2009) Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor–secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol 27:5911–5918

  47. Ercolini AM, Ladle BH, Manning EA et al (2005) Recruitment of latent pools of high-avidity CD8 + T cells to the antitumor immune response. J Exp Med 201:1591–1602

  48. Fisk B, Savary C, Hudson JM et al (1995) Changes in an HER-2 peptide upregulating HLA-A2 expression affect both conformational epitopes and CTL recognition: implications for optimization of antigen presentation and tumor-specific CTL induction. J Immunother Emphasis Tumor Immunol 18:197–209

  49. Förster R, Davalos-Misslitz AC, Rot A (2008) CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8:362–371

  50. Franklin MC, Carey KD, Vajdos FF et al (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5:317–328

  51. Frenzel A, Schirrmann T, Hust M (2016) Phage display-derived human antibodies in clinical development and therapy. MAbs 8:1177–1194

  52. Gao Y, Whitaker-Dowling P, Griffin J et al (2009) Recombinant vesicular stomatitis virus targeted to Her2/neu combined with anti-CTLA4 antibody eliminates implanted mammary tumors. Cancer Gene Ther 16:44–52

  53. Gelao L, Criscitiello C, Esposito A et al (2014) Dendritic cell-based vaccines: clinical applications in breast cancer. Immunotherapy 6:349–360

  54. Gilewski T, Adluri S, Ragupathi G et al (2000) Vaccination of high-risk breast cancer patients with mucin-1 (MUC1) keyhole limpet hemocyanin conjugate plus QS-21. Clin Cancer Res 6:1693–1701

  55. Gillogly ME, Kallinteris NL, Xu M et al (2004) Ii-Key/HER-2/neu MHC class-II antigenic epitope vaccine peptide for breast cancer. Cancer Immunol Immunother 53:490–496

  56. Holmes JP, Benavides LC, Gates JD et al (2008) Results of the first phase I clinical trial of the novel II-key hybrid preventive HER-2/neu peptide (AE37) vaccine. J Clin Oncol 26:3426–3433

  57. Hossain M, Wall K (2016) Immunological evaluation of recent MUC1 glycopeptide cancer vaccines. Vaccines 4(3):E25

  58. Huang Y, Ma C, Zhang Q et al (2015) CD4 + and CD8 + T cells have opposing roles in breast cancer progression and outcome. Oncotarget 6:17462–17478

  59. Jacob J, Radkevich O, Forni G et al (2006) Activity of DNA vaccines encoding self or heterologous Her-2/neu in Her-2 or neu transgenic mice. Cell Immunol 240:96–106

  60. Jaffee EM, Hruban RH, Biedrzycki B et al (2001) Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 19:145–156

  61. Jerome K, Domenech N, Finn O (1993) Tumor-specific cytotoxic T cell clones from patients with breast and pancreatic adenocarcinoma recognize EBV-immortalized B cells transfected with polymorphic epithelial mucin complementary DNA. J Immunol 151:1654–1662

  62. Jinushi M (2015) Immune regulation of cancer stem cells. Nihon Rinsho 73:795–799

  63. Kageyama S, Kitano S, Hirayama M et al (2008) Humoral immune responses in patients vaccinated with 1–146 HER2 protein complexed with cholesteryl pullulan nanogel. Cancer Sci 99:601–607

  64. Kawashima I, Hudson SJ, Tsai V et al (1998) The multi-epitope approach for immunotherapy for cancer: identification of several CTL epitopes from various tumor-associated antigens expressed on solid epithelial tumors. Hum Immunol 59:1–14

  65. Khedri A, Nejat-Shokouhi A, Salek R et al (2011) Association of the colorectal cancer and MDR1 gene polymorphism in an Iranian population. Mol Biol Reports 38(5):2939–2943

  66. Kim JH, Majumder N, Lin H et al (2005) Enhanced immunity by NeuEDhsp70 DNA vaccine is needed to combat an aggressive spontaneous metastatic breast cancer. Mol Ther 11:941–949

  67. Kim E, Seo H, Chae M et al (2014) Enhanced antitumor immunotherapeutic effect of B-cell-based vaccine transduced with modified adenoviral vector containing type 35 fiber structures. Gene Ther 21:106–114

  68. Kim A, Lee SJ, Kim YK et al (2017) Programmed death-ligand 1 (PD-L1) expression in tumour cell and tumour infiltrating lymphocytes of HER2-positive breast cancer and its prognostic value. Sci Rep 7:11671

  69. Kitano S, Kageyama S, Nagata Y et al (2006) HER2-specific T cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan. Clin Cancer Res 12:7397–7405

  70. Knutson KL, Clynes R, Shreeder B et al (2016) Improved survival of HER2 + breast cancer patients treated with trastuzumab and chemotherapy is associated with host antibody immunity against the HER2 intracellular domain. Cancer Res 76:3702–3710

  71. Ko BK, Kawano K, Murray JL et al (2003) Clinical studies of vaccines targeting breast cancer. Clin Cancer Res 9:3222–3234

  72. Krishnamachari Y, Geary SM, Lemke CD et al (2011) Nanoparticle delivery systems in cancer vaccines. Pharm Res 28:215–236

  73. Kroemer G, Senovilla L, Galluzzi L et al (2015) Natural and therapy-induced immunosurveillance in breast cancer. Nat Med 21:1128–1138

  74. Kuerer HM, Peoples GE, Sahin AA et al (2002) Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast. J Interferon Cytokine Res 22:583–592

  75. Kurtz SL, Ravindranathan S, Zaharoff DA (2014) Current status of autologous breast tumor cell-based vaccines. Expert Rev Vaccines 13:1439–1445

  76. Ladjemi MZ, Jacot W, Chardès T et al (2010) Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother 59:1295–1312

  77. Ladjemi MZ, Chardes T, Corgnac S et al (2011) Vaccination with human anti-trastuzumab anti-idiotype scFv reverses HER2 immunological tolerance and induces tumor immunity in MMTV. f. huHER2 (Fo5) mice. Breast Cancer Res 13:R17

  78. Laheru D, Lutz E, Burke J et al (2008) Allogeneic granulocyte macrophage colony-stimulating factor–secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res 14:1455–1463

  79. Leung HW, Chan AL, Muo CH et al (2018) Cost-effectiveness of pertuzumab combined with trastuzumab and docetaxel as a first-line treatment for HER-2 positive metastatic breast cancer. Expert Rev Pharmacoecon Outcomes Res 18:207–213

  80. Li L, Saade F, Petrovsky N (2012) The future of human DNA vaccines. J Biotechnol 162:171–182

  81. Loi S, Giobbie-hurder A, Gombos A et al (2019) Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol 20:371–382

  82. Lollini PL, De Giovanni C, Pannellini T et al (2005) Cancer immunoprevention. Future Oncol 1:57–66

  83. Machiels JP, Reilly RT, Emens LA et al (2001) Cyclophosphamide, doxorubicin, and paclitaxel enhance the antitumor immune response of granulocyte/macrophage-colony stimulating factor-secreting whole-cell vaccines in HER-2/neu tolerized mice. Cancer Res 61:3689–3697

  84. Marchini C, Kalogris C, Garulli C et al (2013) Tailoring DNA vaccines: designing strategies against HER2-positive cancers. Front Oncol 3:122

  85. Marmé F (2016) Immunotherapy in breast cancer. Oncol Res Treat 39:335–345

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

  87. Menotti L, Nicoletti G, Gatta V et al (2009) Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells. Proc Natl Acad Sci USA 106:9039–9044

  88. Miest TS, Cattaneo R (2014) New viruses for cancer therapy: meeting clinical needs. Nat Rev Microbiol 12:23–34

  89. Miliotou AN, Papadopoulou LC (2018) CAR T cell therapy: a new era in cancer immunotherapy. Curr Pharm Biotechno 19:5–18

  90. Mittendorf EA, Storrer CE, Foley RJ et al (2006) Evaluation of the HER2/neu-derived peptide GP2 for use in a peptide-based breast cancer vaccine trial. Cancer 106:2309–2317

  91. Mittendorf EA, Clifton GT, Holmes JP et al (2012) Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer 118:2594–2602

  92. Mittendorf E, Clifton G, Holmes J et al (2014) Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann Oncol 25:1735–1742

  93. Mittendorf BA, Schneble EJ, Ibrahim NK et al (2015) Combination immunotherapy with trastuzumab and the HER2 vaccine E75 (nelipepimut-S) in high-risk HER2 + breast cancer patients to prevent recurrence. Cancer Res 75(Supp 9)

  94. Mittendorf EA, Ardavanis A, Litton JK et al (2016) Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence. Oncotarget 7:66192–66201

  95. Mosaffa F, Kalalinia F, Lage H et al (2012) Pro-inflammatory cytokines interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha alter the expression and function of ABCG2 in cervix and gastric cancer cells. Mol Cell Biochem 363:385–393

  96. Mukai K, Yasutomi Y, Watanabe M et al (2002) HER2 peptide-specific CD8 + T cells are proportionally detectable long after multiple DNA vaccinations. Gene Ther 9:879

  97. Müller P, Kreuzaler M, Khan T et al (2015) Trastuzumab emtansine (T-DM1) renders HER2 + breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med 7:315ra188–315ra188

  98. Nami B, Maadi H, Wang Z (2018) Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers 10(10):E342

  99. Nanda NK, Sercarz EE (1995) Induction of anti-self-immunity to cure cancer. Cell 82:13–17

  100. Nanni P, Gatta V, Menotti L et al (2013) Preclinical therapy of disseminated HER-2 + ovarian and breast carcinomas with a HER-2-retargeted oncolytic herpesvirus. PLoS Pathog 9:e1003155

  101. Nazarkina ZK, Khar’kova M, Antonets D et al (2016) Design of polyepitope DNA vaccine against breast carcinoma cells and analysis of its expression in dendritic cells. Bull Exp Biol Med 160:486–490

  102. Nguyen-Hoai T, Baldenhofer G, Ahmed MS et al (2012a) CCL21 (SLC) improves tumor protection by a DNA vaccine in a Her2/neu mouse tumor model. Cancer Gene Ther 19:69–76

  103. Nguyen-Hoai T, Hohn O, Vu M et al (2012b) CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC. Cancer Gene Ther 19:880

  104. Nordly P, Madsen HB, Nielsen HM et al (2009) Status and future prospects of lipid-based particulate delivery systems as vaccine adjuvants and their combination with immunostimulators. Expert Opin Drug Deliv 6:657–672

  105. Norell H, Poschke I, Charo J et al (2010) Vaccination with a plasmid DNA encoding HER-2/neu together with low doses of GM-CSF and IL-2 in patients with metastatic breast carcinoma: a pilot clinical trial. J Transl Med 8:53

  106. Nourbakhsh M, Jaafari MR, Lage H et al (2015) Nanolipoparticles-mediated MDR1 siRNA delivery reduces doxorubicin resistance in breast cancer cells and silences MDR1 expression in xenograft model of human breast cancer. Iran J Basic Med Sci 18(4):385–392

  107. Pakravan N, Langroudi L, Hajimoradi M et al (2010) Co-administration of GP96 and Her2/neu DNA vaccine in a Her2 breast cancer model. Cell Stress Chaperones 15:977–984

  108. Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265–277

  109. Park JW, Melisko ME, Esserman LJ et al (2007) Treatment with autologous antigen-presenting cells activated with the HER-2–based antigen lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2–overexpressing breast cancer. J Clin Oncol 25:3680–3687

  110. Parvizpour S, Razmara J, Omidi Y (2018) Breast cancer vaccination comes to age: impacts of bioinformatics. BioImpacts 8:223–235

  111. Patil R, Clifton GT, Holmes JP et al (2010) Clinical and immunologic responses of HLA-A3 + breast cancer patients vaccinated with the HER2/neu-derived peptide vaccine, E75, in a phase I/II clinical trial. J Am Coll Surg 210:140–147

  112. Peiper M, Goedegebuure PS, Linehan DC et al (1997) The HER2/neu-derived peptide p654–662 is a tumor-associated antigen in human pancreatic cancer recognized by cytotoxic T lymphocytes. Eur J Immunol 27:1115–1123

  113. Pietras R, Fendly B, Chazin V et al (1994) Antibody to HER-2/neu receptor blocks DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 9:1829–1838

  114. Pietras RJ, Pegram MD, Finn RS et al (1998) Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs. Oncogene 17:2235–2249

  115. Prisco A, De Berardinis P (2012) Filamentous bacteriophage fd as an antigen delivery system in vaccination. Int J Mol Sci 13:5179–5194

  116. Qi H, Egen JG, Huang AY et al (2006) Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312:1672–1676

  117. Raina D, Ahmad R, Joshi MD et al (2009) Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res 69:5133–5141

  118. Raina D, Uchida Y, Kharbanda A et al (2014) Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 33:3422–3431

  119. Razazan A, Behravan J, Arab A et al (2017) Conjugated nanoliposome with the HER2/neu-derived peptide GP2 as an effective vaccine against breast cancer in mice xenograft model. PLoS One 12:e0185099

  120. Razazan A, Nicastro J, Slavcev R et al (2019) Lambda bacteriophage nanoparticles displaying GP2, a HER2/neu derived peptide, induce prophylactic and therapeutic activities against TUBO tumor model in mice. Sci Rep 9:2221

  121. Rovero S, Amici A, Di Carlo E et al (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165:5133–5142

  122. Sabahi Z, Salek R, Heravi RE et al (2010) Association of gastric cancer incidence with MDR1 gene polymorphism in an ethnic Iranian population. Indian J Cancer 47:317–321

  123. Sadri-Ardalani F, Shabani M, Amiri MM et al (2016) Antibody response to HER2 extracellular domain and subdomains in mouse following DNA immunization. Tumour Biol 37:1217–1227

  124. Salgado R, Denkert C, Campbell C et al (2015) Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol 1:448–455

  125. Schmid P, Adams S, Rugo HS et al (2018) Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 379:2108–2121

  126. Scholl SM, Balloul JM, Le Goc G et al (2000) Recombinant vaccinia virus encoding human MUC1 and IL2 as immunotherapy in patients with breast cancer. J Immunother 23:570–580

  127. Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570

  128. Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

  129. Slichenmyer WJ, Fry DW (2001) Anticancer therapy targeting the erbB family of receptor tyrosine kinases. Semin Oncol 28(5 Suppl):67–79

  130. Solinas C, Gombos A, Latifyan S et al (2017) Targeting immune checkpoints in breast cancer: an update of early results. ESMO Open 2:e000255

  131. Sotiropoulou P, Perez S, Iliopoulou E et al (2003) Cytotoxic T cell precursor frequencies to HER-2 (369–377) in patients with HER-2/neu-positive epithelial tumours. Br J Cancer 89:1055–1061

  132. Srivatsan S, Patel JM, Bozeman EN et al (2014) Allogeneic tumor cell vaccines: the promise and limitations in clinical trials. Hum Vaccin Immunother 10:52–63

  133. Stewart TJ, Smyth MJ (2009) Chemokine–chemokine receptors in cancer immunotherapy. Future Med 1:109–127

  134. Su M, Huang CX, Dai AP (2016) Immune checkpoint inhibitors: therapeutic tools for breast cancer. Asian Pac J Cancer Prev 17:905–910

  135. Sugie T, Toi M (2017) Antitumor immunity and advances in cancer immunotherapy. Breast Cancer 24:1–2

  136. Swain SM, Baselga J, Kim SB et al (2015) Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 372:724–734

  137. Takahashi H, Wilson B, Ozturk M et al (1988) In vivo localization of human colon adenocarcinoma by monoclonal antibody binding to a highly expressed cell surface antigen. Cancer Res 48:6573–6579

  138. Tan TJ, Chan JJ, Kamis S et al (2018) What is the role of immunotherapy in breast cancer. Chin J Clin Oncol 7:13

  139. Teulon I, Alvarez N, Behar G et al (2006) 121 POSTER Isolation and characterisation of anti-idiotypic scFv antibody fragments and llama VHH domains used as a surrogate tumour antigen to elicit an anti-HER-2 humoral response in mice. EJC Suppl 4:40

  140. Todryk SM, Gough MJ, Pockley AG (2003) Facets of heat shock protein 70 show immunotherapeutic potential. Immunology 110:1–9

  141. Tomasicchio M, Semple L, Esmail A et al (2019) An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells. Cancer Immunol Immunother 68:71–83

  142. Tran T, Diniz MO, Dransart E et al (2016) A therapeutic Her2/neu vaccine targeting dendritic cells preferentially inhibits the growth of low Her2/neu–expressing tumor in HLA-A2 transgenic mice. Clin Cancer Res 22:4133–4144

  143. Vassilaros S, Tsibanis A, Tsikkinhs A et al (2007) 10 years follow up of pilot phase Iii immunotherapy study in early stage breast cancer patients using oxidized mannan-muc1. Breast Cancer Res Treat 106:S31–S31

  144. Viehl CT, Becker-Hapak M, Lewis JS et al (2005) A Tat fusion protein-based tumor vaccine for breast cancer. Ann Surg Oncol 12:517–525

  145. Viola A, Contento RL, Molon B (2006) T cells and their partners: the chemokine dating agency. Trends Immunol 27:421–427

  146. Wang W, Li Y, Wang Y et al (2018) Polyactin A is a novel and potent immunological adjuvant for peptide-based cancer vaccine. Int Immunopharmacol 54:95–102

  147. Watson DS, Endsley AN, Huang L (2012) Design considerations for liposomal vaccines: influence of formulation parameters on antibody and cell-mediated immune responses to liposome associated antigens. Vaccine 30:2256–2272

  148. Williams AD, Payne KK, Posey AD et al (2017) Immunotherapy for breast cancer: current and future strategies. Curr Surg Rep 5(12):31

  149. Wolchok JD, Hodi FS, Weber JS et al (2013) Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann NY Acad Sci 1291:1–13

  150. Xie Y, Chen Y, Ahmed K et al (2013) Potent CD4 + T cell epitope P30 enhances HER2/neu-engineered dendritic cell-induced immunity against Tg1-1 breast cancer in transgenic FVBneuN mice by enhanced CD4 + T cell-stimulated CTL responses. Cancer Gene Ther 20:590–598

  151. Yang B, Jeang J, Yang A et al (2014) DNA vaccine for cancer immunotherapy. Hum Vaccin Immunother 10:3153–3164

  152. Yazdian-Robati R, Ramezani M, Khedri M et al (2017) An aptamer for recognizing the transmembrane protein PDL-1 (programmed death-ligand 1), and its application to fluorometric single cell detection of human ovarian carcinoma cells. Microchim Acta 184:4029–4035

  153. Yoshino I, Goedegebuure PS, Peoples GE et al (1994) HER2/neu-derived peptides are shared antigens among human non-small cell lung cancer and ovarian cancer. Cancer Res 54:3387–3390

  154. Zhou X, Liu R, Qin S et al (2016) Current status and future directions of nanoparticulate strategy for cancer immunotherapy. Curr Drug Metab 17:755–762

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Correspondence to Javad Behravan.

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Javad Behravan is an adjunct professor at University of Waterloo, Waterloo, Ontario, Canada and Co-founder of Theraphage Inc. Kitchener, Ontario, Canada. The authors declare that they have no conflicts of interests.

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Arab, A., Yazdian-Robati, R. & Behravan, J. HER2-Positive Breast Cancer Immunotherapy: A Focus on Vaccine Development. Arch. Immunol. Ther. Exp. 68, 2 (2020).

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  • Breast cancer
  • HER2
  • Immunotherapy
  • Vaccine