HER2-Specific Vaccines for HER2-Positive Breast Cancer Immunotherapy


Anti-human epidermal growth factor receptor-2 (HER2) immunization can be elicited by vaccination with DNA encoding the extra- or intra-cellular domain (ECD or ICD) of HER2, naked or encap-sulated in viral vectors. HER2-peptides derived from ECD or ICD of HER2, and HER2-pulsed dendritic cells (DCs) or engineered DCs expressing HER2, respectively. We performed a computer- based literature search which includes but is not limited to the following keywords: breast cancer, immunotherapy, HER2-peptide vaccine, HER2-DNA vaccine, HER-DC vaccine, HER2 vaccine, and HER2/neu, in PubMed, Medline, EMBO and Google Scholar; data from recently reported clinical trials were also included. Drawing upon this synthesis of literature, this work summarizes the de-velopment and current trend in experimental and clinical investigations in HER2-positive breast cancer using HER2-specific vaccine and immunotherapy, focusing especially on: (i) DNA-; (ii) peptide-; and (iii) DC-based vaccines. It addresses interventions that have been applied to overcome immunotolerance thereby to improve treatment outcomes. These include blocking the inhibitory cytotoxic T lymphocyte-associated protein-4 (CTLA-4), which is expressed at high levels by regulatory T (Treg) cells, or complete Treg depletion to improve T-cell activation. Moreover, modulatory interventions can provide further improvement in the efficacy of HER2-specific vaccine. The interventions include the use of immunogenic adjuvants such as cytokines interleukin-12 (IL-12), tumor necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (GM-CSF), the use of Toll-like receptor (TLR) ligands and tetanus toxin’s universal epitopes such as the CD4+ help T (Th)-epitope P30, and the use of either chimeric or heterogenous xenogeneic HER2. Combining active HER2-vaccination with adoptive trastuzumab antibody immunotherapy is likely to increase the effectiveness of each approach alone. The development of effective HER2-vaccines for breast cancer remains a critical challenge. Though these novel interventions seem promising, further investigation is still needed since the results are preliminary. Furthermore, the review discusses the challenges and future perspectives in HER2-vaccine research and development.

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Omabe, M. , Ahmed, S. , Sami, A. , Xie, Y. , Tao, M. and Xiang, J. (2015) HER2-Specific Vaccines for HER2-Positive Breast Cancer Immunotherapy. World Journal of Vaccines, 5, 106-128. doi: 10.4236/wjv.2015.52013.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Wieduwilt, M.J. and Moasser, M.M. (2008) The Epidermal Growth Factor Receptor Family: Biology Driving Targeted Therapeutics. Cellular and Molecular Life Sciences, 65, 1566-1584.
[2] Hynes, N.E. and MacDonald, G. (2009) ErbB Receptors and Signaling Pathways in Cancer. Current Opinion in Cell Biology, 21, 177-184.
[3] Milani, A., Sangiolo, D., Montemurro, F., Aglietta, M. and Valabrega, G. (2013) Active Immunotherapy in HER2 Overexpressing Breast Cancer: Current Status and Future Perspectives. Annals of Oncology, 24, 1740-1748.
[4] Tebbutt, N., Pedersen, M.W. and Johns, T.G. (2013) Targeting the ERBB Family in Cancer: Couples Therapy. Nature Reviews Cancer, 13, 663-673.
[5] Yarden, Y. and Pines, G. (2012) The ERBB Network: At Last, Cancer Therapy Meets Systems Biology. Nature Reviews Cancer, 12, 553-563.
[6] Kirouac, D.C., Du, J.Y., Lahdenranta, J., Overland, R., Yarar, D., Paragas, V., Pace E., McDonagh, C.F., Nielsen, U.B. and Onsum, M.D. (2013) Computational Modeling of ERBB2-Amplified Breast Cancer Identifies Combined ErbB2/3 Blockade as Superior to the Combination of MEK and AKT Inhibitors. Science Signaling, 6, ra68.
[7] Hynes, N.E. and Lane, H.A. (2005) ERBB Receptors and Cancer: The Complexity of Targeted Inhibitors. Nature Reviews Cancer, 5, 341-354.
[8] Bailey, T.A., Luan, H., Clubb, R.J., Naramura, M., Band, V., Raja, S.M. and Band, H. (2011) Mechanisms of Trastuzumab Resistance in ErbB2-Driven Breast Cancer and Newer Opportunities to Overcome Therapy Resistance. Journal of Carcinogenesis, 10, 28.
[9] Jackson, C., Browell, D., Gautrey, H. and Tyson-Capper, A. (2013) Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance. International Journal of Cell Biology, 2013, Article ID: 973584.
[10] Hart, M.R., Su, H.Y., Broka, D., Goverdhan, A. and Schroeder, J.A. (2013) Inactive ERBB Receptors Cooperate with Reactive Oxygen Species to Suppress Cancer Progression. Molecular Therapy, 21, 1996-2007.
[11] Yarden, Y. and Sliwkowski, M.X. (2001) Untangling the ErbB Signalling Network. Nature Reviews Molecular Cell Biology, 2, 127-137.
[12] Montemurro, F. and Scaltriti, M. (2014) Biomarkers of Drugs Targeting HER-Family Signalling in Cancer. Journal of Pathology, 232, 219-229.
[13] Schechter, A.L., Hung, M.C., Vaidyanathan, L., Weinberg, R.A., Yang-Feng, T.L., Francke, U., Ullrich, A. and Coussens, L. (1985) The Neu Gene: An ErbB-Homologous Gene Distinct from and Unlinked to the Gene Encoding the EGF Receptor. Science, 229, 976-978.
[14] Dendukuri, N., Khetani, K., McIsaac, M. and Brophy, J. (2007) Testing for HER2-Positive Breast Cancer: A Systematic Review and Cost-Effectiveness Analysis. Canadian Medical Association Journal, 176, 1429-1434.
[15] Ross, J.S., Slodkowska, E.A., Symmans, W.F., Pusztai, L., Ravdin, P.M. and Hortobagyi, G.N. (2009) The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti-HER-2 Therapy and Personalized Medicine. Oncologist, 14, 320-368.
[16] Dawood, S., Broglio, K., Buzdar, A.U., Hortobagyi, G.N. and Giordano, S.H. (2010) Prognosis of Women with Metastatic Breast Cancer by HER2 Status and Trastuzumab Treatment: An Institutional-Based Review. Journal of Clinical Oncology, 28, 92-98.
[17] Olson, E.M. (2012) Maximizing Human Epidermal Growth Factor Receptor 2 Inhibition: A New Oncologic Paradigm in the Era of Targeted Therapy. Journal of Clinical Oncology, 30, 1712-1714.
[18] Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J., Ullrich, A. and McGuire, W.L. (1987) Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/Neu Oncogene. Science, 235, 177-182.
[19] Kumar, G. and Badve, S. (2008) Milestones in the Discovery of HER2 Proto-Oncogene and Trastuzumab (Herceptin). Connection, 13, 9-14.
[20] Carter, P., Presta, L., Gorman, C.M., Ridgway, J.B., Henner, D., Wong, W.L., Rowland, A.M., Kotts, C., Carver, M.E. and Shepard, H.M. (1992) Humanization of an Anti-p185HER2 Antibody for Human Cancer Therapy. Proceedings of the National Academy of Sciences of the United States of America, 89, 4285-4289.
[21] Hudis, C.A. (2007) Trastuzumab—Mechanism of Action and Use in Clinical Practice. New England Journal of Medicine, 357, 39-51.
[22] Lollini, P.L. and Forni, G. (2003) Cancer Immunoprevention: Tracking Down Persistent Tumor Antigens. Trends in Immunology, 24, 62-66.
[23] Finn, O.J. (2003) Cancer Vaccines: Between the Idea and the Reality. Nature Reviews Immunology, 3, 630-641.
[24] Lollini, P.L., Cavallo, F., Nanni, P. and Forni, G. (2006) Vaccines for Tumour Prevention. Nature Reviews Cancer, 6, 204-216.
[25] Cavallo, F.D., Giovanni, C., Nanni, P., Forni, G. and Lollini, P.L. (2011) 2011: The Immune Hallmarks of Cancer. Cancer Immunology, Immunotherapy, 60, 319-326.
[26] Whittington, P.J., Radkevich, B.O., Jacob, J.B., Jones, R.F., Weise, A.M. and Wei, W.Z. (2009) Her-2 DNA versus Cell Vaccine: Immunogenicity and Anti-Tumor Activity. Cancer Immunology, Immunotherapy, 58, 759-767.
[27] Bodles-Brakhop, A.M., Heller, R. and Draghia-Akli, R. (2009) Electroporation for the Delivery of DNA-Based Vaccines and Immunotherapeutics: Current Clinical Developments. Molecular Therapy, 17, 585-592.
[28] Liu, M.A. (2003) DNA Vaccines: A Review. Journal of Internal Medicine, 253, 402-410.
[29] Radkevich-Brown, O., Jacob, J., Kershaw, M. and Wei, W.Z. (2009) Genetic Regulation of the Response to Her-2 DNA Vaccination in Human Her-2 Transgenic Mice. Cancer Research, 69, 212-218.
[30] Nguyen-Hoai, T., Kobelt, D., Hohn, O., Vu, M.D., Schlag, P.M., Dorken, B., Norley, S., Lipp, M., Walther, W., Pezzutto, A. and Westermann, J. (2012) HER2/Neu DNA Vaccination by Intradermal Gene Delivery in a Mouse Tumor Model: Gene Gun Is Superior to Jet Injector in Inducing CTL Responses and Protective Immunity. OncoImmunology, 1, 1537-1545.
[31] Wei, W.Z., Shi, W.P., Galy, A., Lichlyter, D., Hernandez, S., Groner, B., Heilbrun, L. and Jones, R.F. (1999) Protection against Mammary Tumor Growth by Vaccination with Full-Length, Modified Human ErbB-2 DNA. International Journal of Cancer, 81, 748-754.
[32] Pilon, S.A., Piechocki, M.P. and Wei, W.Z. (2001) Vaccination with Cytoplasmic ErbB-2 DNA Protects Mice from Mammary Tumor Growth without Anti-ErbB-2 Antibody. Journal of Immunology, 167, 3201-3206.
[33] Pupa, S.M., Iezzi, M., Di, C.E., Invernizzi, A., Cavallo, F., Meazza, R., Comes, A., Ferrini, S., Musiani, P. and Ménard, S. (2005) Inhibition of Mammary Carcinoma Development in HER-2/Neu Transgenic Mice through Induction of Autoimmunity by Xenogeneic DNA Vaccination. Cancer Research, 65, 1071-1078.
[34] Jacob, J.B., Kong, Y.C., Nalbantoglu, I., Snower, D.P. and Wei, W.Z. (2009) Tumor Regression Following DNA Vaccination and Regulatory T Cell Depletion in Neu Transgenic Mice Leads to an Increased Risk for Autoimmunity. Journal of Immunology, 182, 5873-5881.
[35] Fioretti, D., Iurescia, S., Fazio, V.M. and Rinaldi, M. (2010) DNA Vaccines: Developing New Strategies against Cancer. Journal of Biomedicine and Biotechnology, 2010, Article ID: 174378.
[36] Chen, Y., Hu, D., Eling, D.J., Robbins, J. and Kipps, T.J. (1998) DNA Vaccines Encoding Full-Length or Truncated Neu Induce Protective Immunity against Neu-Expressing Mammary Tumors. Cancer Research, 58, 1965-1971.
[37] Cao, J., Jin, Y., Li, W., Zhang, B., He, Y., Liu, H., Xia, N., Wei, H. and Yan, J. (2013) DNA Vaccines Targeting the Encoded Antigens to Dendritic Cells Induce Potent Antitumor Immunity in Mice. BMC Immunology, 14, 39.
[38] Jacob, J.B., Quaglino, E., Radkevich-Brown, O., Jones, R.F., Piechocki, M.P., Reyes, J.D., et al. (2010) Combining Human and Rat Sequences in HER-2 DNA Vaccines Blunts Immune Tolerance and Drives Antitumor Immunity. Cancer Research, 70, 119-128.
[39] Occhipinti, S., Sponton, L., Rolla, S., Caorsi, C., Novarino, A., Donadio, M., Bustreo, S., Satolli, M.A., Pecchioni, C., Marchini, C., Amici, A., Cavallo, F., Cappello, P., Pierobon, D., Novelli, F. and Giovarelli, M. (2014) Chimeric Rat/Human HER2 Efficiently Circumvents HER2 Tolerance in Cancer Patients. Clinical Cancer Research, 20, 2910- 2921.
[40] Collison, L.W., Workman, C.J., Kuo, T.T., Boyd, K., Wang, Y., Vignali, K.M., Cross, R., Sehy, D., Blumberg, R.S. and Vignali, D.A. (2007) The Inhibitory Cytokine IL-35 Contributes to Regulatory T-Cell Function. Nature, 450, 566- 569.
[41] Wei, H., Wang, S., Zhang, D., Hou, S., Qian, W., Li, B., Guo, H., Kou, G., He, J., Wang, H. and Guo, Y. (2009) Targeted Delivery of Tumor Antigens to Activated Dendritic Cells via CD11c Molecules Induces Potent Antitumor Immunity in Mice. Clinical Cancer Research, 15, 4612-4621.
[42] Wei, W.Z., Jacob, J.B., Zielinski, J.F., Flynn, J.C., Shim, K.D., Alsharabi, G., Giraldo, A.A. and Kong, Y.C. (2005) Concurrent Induction of Antitumor Immunity and Autoimmune Thyroiditis in CD4+CD25+ Regulatory T Cell-De- pleted Mice. Cancer Research, 65, 8471-8478.
[43] de León, J., Fernández, A., Clavell, M., Labrada, M., Bebelagua, Y., Mesa, C. and Fernández, L.E. (2008) Differential Influence of the Tumour-Specific Non-Human Sialic Acid Containing GM3 Ganglioside on CD4+CD25 Effector and Naturally Occurring CD4+ CD25+ Regulatory T Cells Function. International Immunology, 20, 591-600.
[44] Rolla, S., Ria, F., Occhipinti, S., Di Sante, G., Iezzi, M., Spadaro, M., Nicolò, C., Ambrosino, E., Merighi, I.F., Musiani, P., Forni, G. and Cavallo, F. (2010) Erbb2 DNA Vaccine Combined with Regulatory T Cell Deletion Enhances Antibody Response and Reveals Latent Low-Avidity T Cells: Potential and Limits of Its Therapeutic Efficacy. Journal of Immunology, 184, 6124-6132.
[45] Emens, L.A., Asquith, J.M., Leatherman, J.M., Kobrin, B.J., Petrik, S., Laiko, M., Levi, J., Daphtary, M.M., Biedrzycki, B., Wolff, A.C., Stearns, V., Disis, M.L., Ye, X., Piantadosi, S., Fetting, J.H., Davidson, N.E. and Jaffee, E.M. (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. Journal of Clinical Oncology, 27, 5911-5918.
[46] Norell, H., Poschke, I., Charo, J., Wei, W.Z., Erskine, C., Piechocki, M.P., Knutson, K.L., Bergh, J., Lidbrink, E. and Kiessling, R. (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. Journal of Translational Medicine, 8, 53.
[47] Ladjemi, M.Z., Jacot, W., Chardès, T., Pèlegrin, A. and Navarro-Teulon, I. (2010) Anti-HER2 Vaccines: New Prospects for Breast Cancer Therapy. Cancer Immunology, Immunotherapy, 59, 1295-1312.
[48] Diaz, C.M., Chiappori, A., Aurisicchio, L., Bagchi, A., Clark, J., Dubey, S., Fridman, A., Fabregas, J.C., Marshall, J., Scarselli, E., La Monica, N., Ciliberto, G. and Montero, A.J. (2013) Phase I Studies of the Safety and Immunogenicity of Electroporated HER2/CEA DNA Vaccine Followed by Adenoviral Boost Immunization in Patients with Solid Tumors. Journal of Translational Medicine, 11, 62.
[49] Provinciali, M., Smorlesi, A., Donnini, A., Bartozzi, B. and Amici, A. (2003) Low Effectiveness of DNA Vaccination against HER-2/Neu in Ageing. Vaccine, 21, 843-848.
[50] Provinciali, M., Barucca, A., Pierpaoli, E., Orlando, F., Pierpaoli, S. and Smorlesi, A. (2012) In Vivo Electroporation Restores the Low Effectiveness of DNA Vaccination against HER-2/Neu in Aging. Cancer Immunology, Immunotherapy, 61, 363-371.
[51] Quaglino, E., Iezzi, M., Mastini, C., Amici, A., Pericle, F., Di Carlo, E., Pupa, S.M., De Giovanni, C., Spadaro, M., Curcio, C., Lollini, P.L., Musiani, P., Forni, G. and Cavallo, F. (2004) Electroporated DNA Vaccine Clears Away Multifocal Mammary Carcinomas in Her-2/Neu Transgenic Mice. Cancer Research, 64, 2858-2864.
[52] Aichele, P., Hengartner, H., Zinkernagel, R.M. and Schulz, M. (1990) Antiviral Cytotoxic T Cell Response Induced by in Vivo Priming with a Free Synthetic Peptide. Journal of Experimental Medicine, 171, 1815-1820.
[53] Ossevoort, M.A., Feltkamp, M.C., Veen, K.J., Melief, C.J. and Kast, W.M. (1995) Dendritic Cells as Carriers for a Cytotoxic T-Lymphocyte Epitope-Based Peptide Vaccine in Protection against a Human Papillomavirus Type 16-Induced Tumor. Journal of Immunotherapy with Emphasis on Tumor Immunology, 18, 86-94.
[54] Melief, C.J. and Burg, S.H. (2008) Immunotherapy of Established (Pre)malignant Disease by Synthetic Long Peptide Vaccines. Nature Reviews Cancer, 8, 351-360.
[55] Rosenberg, S.A., Yang, J.C. and Restifo, N.P. (2004) Cancer Immunotherapy: Moving beyond Current Vaccines. Nature Medicine, 10, 909-915.
[56] Bijker, M.S., Eeden, S.J., Franken, K.L., Melief, C.J., Offringa, R. and Burg, S.H. (2007) CD8+ CTL Priming by Exact Peptide Epitopes in Incomplete Freund’s Adjuvant Induces a Vanishing CTL Response, Whereas Long Peptides Induce Sustained CTL Reactivity. Journal of Immunology, 179, 5033-5040.
[57] Schulz, M., Zinkernagel, R.M. and Hengartner, H. (1991) Peptide-Induced Antiviral Protection by Cytotoxic T Cells. Proceedings of the National Academy of Sciences of the United States of America, 88, 991-993.
[58] Fayolle, C., Deriaud, E. and Leclerc, C. (1991) In Vivo Induction of Cytotoxic T Cell Response by a Free Synthetic Peptide Requires CD4+ T Cell Help. Journal of Immunology, 147, 4069-4073.
[59] Schuurhuis, D.H., Laban, S., Toes, R.E., Ricciardi-Castagnoli, P., Kleijmeer, M.J., Voort, E.I., Rea, D., Offringa, R., Geuze, H.J., Melief, C.J. and Ossendorp, F. (2000) Immature Dendritic Cells Acquire CD8+ Cytotoxic T Lymphocyte Priming Capacity upon Activation by T Helper Cell-Independent or -Dependent Stimuli. Journal of Experimental Medicine, 192, 145-150.
[60] Scheibenbogen, C., Schadendorf, D., Bechrakis, N.E., Nagorsen, D., Hofmann, U., Servetopoulou, F., Letsch, A., Philipp, A., Foerster, M.H., Schmittel, A., Thiel, E. and Keilholz, U. (2003) Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Foreign Helper Protein as Immunologic Adjuvants on the T-Cell Response to Vaccination with Tyrosinase Peptides. International Journal of Cancer, 104, 188-194.
[61] Block, M.S., Suman, V.J., Nevala, W.K., Kottschade, L.A., Creagan, E.T., Kaur, J.S., Quevedo, J.F., McWilliams, R.R. and Markovic, S.N. (2011) Pilot Study of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 as Immune Adjuvants for a Melanoma Peptide Vaccine. Melanoma Research, 21, 438-445.
[62] Welters, M.J., Bijker, M.S., Eeden, S.J., Franken, K.L., Melief, C.J., Offringa, R. and Burg, S.H. (2007) Multiple CD4 and CD8 T-Cell Activation Parameters Predict Vaccine Efficacy in Vivo Mediated by Individual DC-Activating Agonists. Vaccine, 25, 1379-1389.
[63] Speiser, D.E., Liénard, D., Rufer, N., Rubio-Godoy, V., Rimoldi, D., Lejeune, F., Krieg, A.M., Cerottini, J.C. and Romero, P. (2005) Rapid and Strong Human CD8+ T Cell Responses to Vaccination with Peptide, IFA, and CpG Oligodeoxynucleotide 7909. Journal of Clinical Investigation, 115, 739-746.
[64] Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. and Lanzavecchia, A. (2005) Selected Toll-Like Receptor Agonist Combinations Synergistically Trigger a T Helper Type 1-Polarizing Program in Dendritic Cells. Nature Immunology, 6, 769-776.
[65] Boer, A.T., Diehl, L., van, Mierlo, G.J., Voort, E.I., Fransen, M.F., Krimpenfort, P., Melief, C.J., Offringa, R. and Toes, R.E. (2001) Longevity of Antigen Presentation and Activation Status of APC Are Decisive Factors in the Balance between CTL Immunity versus Tolerance. Journal of Immunology, 167, 2522-2528.
[66] Khan, S., Bijker, M.S., Weterings, J.J., Tanke, H.J., Adema, G.J., Drijfhout, J.W., Melief, C.J., Overkleeft, H.S., Marel, G.A., Filippov, D.V., Burg, S.H. and Ossendorp, F. (2007) Distinct Uptake Mechanisms but Similar Intracellular Processing of Two Different Toll-Like Receptor Ligand-Peptide Conjugates in Dendritic Cells. Journal of Biological Chemistry, 282, 21145-21159.
[67] Jackson, D.C., Lau, Y.F., Le, T., Suhrbier, A., Deliyannis, G., Cheers, C., Smith, C., Zeng, W. and Brown, L.E. (2004) A Totally Synthetic Vaccine of Generic Structure that Targets Toll-Like Receptor 2 on Dendritic Cells and Promotes Antibody or Cytotoxic T Cell Responses. Proceedings of the National Academy of Sciences of the United States of America, 101, 15440-15445.
[68] Zwaveling, S., Ferreira, M.S., Nouta, J., Johnson, M., Lipford, G.B., Offringa, R., Burg, S.H. and Melief, C.J. (2002) Established Human Papillomavirus Type 16-Expressing Tumors Are Effectively Eradicated Following Vaccination with Long Peptides. Journal of Immunology, 169, 350-358.
[69] Peoples, G.E., Holmes, J.P., Hueman, M.T., Mittendorf, E.A., Amin, A., Khoo, S., Dehqanzada, Z.A., Gurney, J.M., Woll, M.M., Ryan, G.B., Storrer, C.E., Craig, D., Ioannides, C.G. and Ponniah, S. (2008) Combined Clinical Trial Results of a HER2/Neu (E75) Vaccine for the Prevention of Recurrence in High-Risk Breast Cancer Patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clinical Cancer Research, 14, 797-803.
[70] Benavides, L.C., Sears, A.K., Gates, J.D., Clifton, G.T., Clive, K.S., Carmichael, M.G., Holmes, J.P., Mittendorf, E.A., Ponniah, S. and Peoples, G.E. (2011) Comparison of Different HER2/Neu Vaccines in Adjuvant Breast Cancer Trials: Implications for Dosing of Peptide Vaccines. Expert Review of Vaccines, 10, 201-210.
[71] Mittendorf, E.A., Clifton, G.T., Holmes, J.P., Clive, K.S., Patil, R., Benavides, L.C., Gates, J.D., Sears, A.K., Stojadinovic, A., Ponniah, S. and Peoples, G.E. (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.
[72] Peoples, G.E., Goedegeburre, P.S., Smith, R., Linehan, D.C., Yoshino, I. and Eberlein, T.J. (1995) Breast and Ovarian Cancer-Specific Cytotoxic T Lymphocytes Recognize the Same HER2/Neu-Derived Peptide. Proceedings of the National Academy of Sciences of the United States of America, 92, 432-436.
[73] Schneble, E.J., Berry, J.S., Trappey, F.A., Clifton, G.T., Ponniah, S., Mittendorf, E. and Peoples, G.E. (2014) The HER2 Peptide Nelipepimut-S (E75) Vaccine (NeuVax) in Breast Cancer Patients at Risk for Recurrence: Correlation of Immunologic Data with Clinical Response. Immunotherapy, 6, 519-531.
[74] Mittendorf, E.A., Clifton, G.T., Holmes, J.P., Schneble, E., Echo, D., Ponniah, S. and Peoples, G.E. (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. Annals of Oncology, 25, 1735-1742.
[75] Zaks, T.Z. and Rosenberg, S.A. (1998) Immunization with a Peptide Epitope (p369-377) from HER-2/Neu Leads to Peptide-Specific Cytotoxic T Lymphocytes that Fail to Recognize HER-2/Neu+ Tumors. Cancer Research, 58, 4902- 4908.
[76] Peoples, G.E., Gurney, J.M., Hueman, M.T., Woll, M.M., Ryan, G.B., Storrer, C.E., Fisher, C., Shriver, C.D., Ioannides, C.G. and Ponniah, S. (2005) Clinical Trial Results of a HER2/Neu (E75) Vaccine to Prevent Recurrence in High-Risk Breast Cancer Patients. Journal of Clinical Oncology, 23, 7536-7545.
[77] Knutson, K.L., Schiffman, K. and Disis, M.L. (2001) Immunization with a HER-2/Neu Helper Peptide Vaccine Generates HER-2/Neu CD8 T-Cell Immunity in Cancer Patients. Journal of Clinical Investigation, 107, 477-484.
[78] Disis, M.L., Gooley, T.A., Rinn, K., Davis, D., Piepkorn, M., Cheever, M.A., Knutson, K.L. and Schiffman, K. (2002) Generation of T-Cell Immunity to the HER-2/Neu Protein after Active Immunization with HER-2/Neu Peptide-Based Vaccines. Journal of Clinical Oncology, 20, 2624-2632.
[79] Salazar, L.G., Goodell, V., O’Meara, M., Knutson, K., Dang, Y., Rosa, C., Guthrie, K. and Disis, M.L. (2009) Persistent Immunity and Survival after Immunization with a HER2/Neu (HER2) Vaccine. ASCO Meeting Abstracts, 27, 3010.
[80] Amin, A., Benavides, L.C., Holmes, J.P., Gates, J.D., Carmichael, M.G., Hueman, M.T., Mittendorf, E.A., Storrer, C.E., Jama, Y.H., Craig, D., Stojadinovic, A., Ponniah, S. and Peoples, G.E. (2008) Assessment of Immunologic Response and Recurrence Patterns among Patients with Clinical Recurrence after Vaccination with a Preventive HER2/Neu Peptide Vaccine: From US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer Immunology, Immunotherapy, 57, 1817-1825.
[81] Clive, K.S., Tyler, J.A., Clifton, G.T., Holmes, J.P., Ponniah, S., Peoples, G.E. and Mittendorf, E.A. (2012) The GP2 Peptide: A HER2/Neu-Based Breast Cancer Vaccine. Journal of Surgical Oncology, 105, 452-458.
[82] Mittendorf, E.A., Holmes, J.P., Ponniah, S. and Peoples, G.E. (2008) The E75 HER2/Neu Peptide Vaccine. Cancer Immunology, Immunotherapy, 57, 1511-1521.
[83] Dang, Y., Knutson, K.L., Goodell, V., Rosa, C., Salazar, L.G., Higgins, D., Childs, J. and Disis, M.L. (2007) Tumor Antigen-Specific T-Cell Expansion Is Greatly Facilitated by in Vivo Priming. Clinical Cancer Research, 13, 1883- 1891.
[84] Clifton, G.T., Holmes, J.P., Perez, S.A., Lorentz, D., Georgakopoulou, K., Benavides, L., Gates, J., Mittendorf, M., Ardavanis, A., Gritzapis, A., Ponniah, S., Papamichail, M. and Peoples, G. (2009) Interim Analysis of a Randomized Phase II Study of the Novel HER2/Neu Peptide (GP2) Vaccine to Prevent Breast Cancer Recurrence: United States Military Cancer Institute Clinical Trials Group Study I-05. Cancer Research, 69 (24 Suppl), Abstract No. 5110.
[85] Hung, K., Hayashi, R., Lafond-Walker, A., Lowenstein, C., Pardoll, D. and Levitsky, H. (1998) The Central Role of CD4+ T Cells in the Antitumor Immune Response. Journal of Experimental Medicine, 188, 2357-2368.
[86] Hu, H.M., Winter, H., Urba, W.J. and Fox, B.A. (2000) Divergent Roles for CD4+ T Cells in the Priming and Effector/ Memory Phases of Adoptive Immunotherapy. Journal of Immunology, 165, 4246-4253.
[87] Protti, M.P., Monte, L.D. and Lullo, G.D. (2014) Tumor Antigen-Specific CD4+ T Cells in Cancer Immunity: From Antigen Identification to Tumor Prognosis and Development of Therapeutic Strategies. Tissue Antigens, 83, 237-246.
[88] Sears, A.K., Perez, S.A., Clifton, G.T., Benavides, L.C., Gates, J.D., Clive, K.S., Holmes, J.P., Shumway, N.M., Van Echo, D.C., Carmichael, M.G., Ponniah, S., Baxevanis, C.N., Mittendorf, E.A., Papamichail, M. and Peoples, G.E. (2011) AE37: A Novel T-Cell-Eliciting Vaccine for Breast Cancer. Expert Opinion on Biological Therapy, 11, 1543- 1550.
[89] Wiedermann, U., Davis, A.B. and Zielinski, C.C. (2013) Vaccination for the Prevention and Treatment of Breast Cancer with Special Focus on Her-2/Neu Peptide Vaccines. Breast Cancer Research and Treatment, 138, 1-12.
[90] Mittendorf, E.A., Holmes, J.P., Murray, J.L., Hofe, E. and Peoples, G.E. (2009) CD4+ T Cells in Antitumor Immunity: Utility of an Li-Key HER2/Neu Hybrid Peptide Vaccine (AE37). Expert Opinion on Biological Therapy, 9, 71-78.
[91] Gates, J.D., Clifton, G.T., Benavides, L.C., Sears, A.K., Carmichael, M.G., Hueman, M.T., Holmes, J.P., Jama, Y.H., Mursal, M., Zacharia, A., Ciano, K., Khoo, S., Stojadinovic, A., Ponniah, S. and Peoples, G.E. (2010) Circulating Regulatory T Cells (CD4+CD25+FOXP3+) Decrease in Breast Cancer Patients after Vaccination with a Modified MHC Class II HER2/Neu (AE37) Peptide. Vaccine, 28, 7476-7482.
[92] Xu, M. and Kallinteris, N.L. (2012) CD4+ T-Cell Activation for Immunotherapy of Malignancies Using Ii-Key/MHC Class II Epitope Hybrid Vaccines. Vaccine, 30, 2805-2810.
[93] Holmes, J.P., Benavides, L.C., Gates, J.D., Carmichael, M.G., Hueman, M.T., Mittendorf, E.A., Murray, J.L., Amin, A., Craig, D., Hofe, E., Ponniah, S. and Peoples, G.E. (2008) Results of the First Phase I Clinical Trial of the Novel II-Key Hybrid Preventive HER-2/Neu Peptide (AE37) Vaccine. Journal of Clinical Oncology, 26, 3426-3433.
[94] Baxevanis, C.N., Papamichail, M. and Perez, S.A. (2014) Therapeutic Cancer Vaccines: A Long and Winding Road to Success. Expert Review of Vaccines, 13, 131-144.
[95] Zhang, X., Gordon, J.R. and Xiang, J. (2002) Advances in Dendritic Cell-Based Vaccine of Cancer. Cancer Biotherapy and Radiopharmaceuticals, 17, 601-619.
[96] Merad, M., Sathe, P., Helft, J., Miller, J. and Mortha, A. (2013) The Dendritic Cell Lineage: Ontogeny and Function of Dendritic Cells and Their Subsets in the Steady State and the Inflamed Setting. Annual Review of Immunology, 31, 563-604.
[97] Fong, L. and Engleman, E.G. (2000) Dendritic Cells in Cancer Immunotherapy. Annual Review of Immunology, 18, 245-273.
[98] Palucka, K. and Banchereau, J. (2012) Cancer Immunotherapy via Dendritic Cells. Nature Reviews Cancer, 12, 265-277.
[99] Blattman, J.N. and Greenberg, P.D. (2004) Cancer Immunotherapy: A Treatment for the Masses. Science, 305, 200-205.
[100] Galluzzi, L., Senovilla, L., Vacchelli, E., Eggermont, A., Fridman, W.H., Galon, J., Sautès-Fridman, C., Tartour, E., Zitvogel, L. and Kroemer, G. (2012) Trial Watch: Dendritic Cell-Based Interventions for Cancer Therapy. OncoImmunology, 1, 1111-1134.
[101] Tyagi, R.K., Mangal, S., Garg, N. and Sharma, P.K. (2009) RNA-Based Immunotherapy of Cancer: Role and Therapeutic Implications of Dendritic Cells. Expert Review of Anticancer Therapy, 9, 97-114.
[102] Zappasodi, R., Pupa, S.M., Ghedini, G.C., Bongarzone, I., Magni, M., Cabras, A.D., Colombo, M.P., Carlo-Stella, C., Gianni, A.M. and Nicola, M. (2010) Improved Clinical Outcome in Indolent B-Cell Lymphoma Patients Vaccinated with Autologous Tumor Cells Experiencing Immunogenic Death. Cancer Research, 70, 9062-9072.
[103] Vacchelli, E., Vitale, I., Eggermont, A., Fridman, W.H., Fuíková, J., Cremer, I., Galon, J., Tartour, E., Zitvogel, L., Kroemer, G. and Galluzzi, L. (2013) Trial Watch: Dendritic Cell-Based Interventions for Cancer Therapy. OncoImmunology, 2, e25771.
[104] Sun, J.C. and Bevan, M.J. (2003) Defective CD8 T Cell Memory Following Acute Infection without CD4 T Cell Help. Science, 300, 339-342.
[105] Dunkle, A., Dzhagalov, I., Gordy, C. and He, Y.W. (2013) Transfer of CD8+ T Cell Memory Using Bcl-2 as a Marker. Journal of Immunology, 190, 940-947.
[106] Harlin, H., Meng, Y., Peterson, A.C., Zha, Y., Tretiakova, M., Slingluff, C., McKee, M. and Gajewski, T.F. (2009) Chemokine Expression in Melanoma Metastases Associated with CD8+ T-Cell Recruitment. Cancer Research, 69, 3077-3085. http://dx.doi.org/10.1158/0008-5472.CAN-08-2281
[107] Sakai, Y., Morrison, B.J., Burke, J.D., Park, J.M., Terabe, M., Janik, J.E., Forni, G., Berzofsky, J.A. and Morris, J.C. (2004) Vaccination by Genetically Modified Dendritic Cells Expressing a Truncated Neu Oncogene Prevents Development of Breast Cancer in Transgenic Mice. Cancer Research, 64, 8022-8028.
[108] Viehl, C.T., Becker-Hapak, M., Lewis, J.S., Tanaka, Y., Liyanage, U.K., Linehan, D.C., Eberlein, T.J. and Goedegebuure, P.S. (2005) A Tat Fusion Protein-Based Tumor Vaccine for Breast Cancer. Annals of Surgical Oncology, 12, 517-525.
[109] Chen, Y., Emtage, P., Zhu, Q., Foley, R., Muller, W., Hitt, M., Gauldie, J. and Wan, Y. (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 Therapy, 8, 316-323.
[110] Tatsumi, T., Takehara, T., Yamaguchi, S., Sasakawa, A., Miyagi, T., Jinushi, M., Sakamori, R., Kohga, K., Uemura, A., Ohkawa, K., Storkus, W.J. and Hayashi, N. (2007) Injection of IL-12 Gene-Transduced Dendritic Cells into Mouse Liver Tumor Lesions Activates both Innate and Acquired Immunity. Gene Therapy, 14, 863-871.
[111] Chen, Z., Huang, H., Chang, T., Carlsen, S., Saxena, A., Marr, R., Xing, Z. and Xiang, J. (2002) Enhanced HER-2/Neu-Specific Antitumor Immunity by Cotransduction of Mouse Dendritic Cells with Two Genes Encoding HER-2/Neu and Alpha Tumor Necrosis Factor. Cancer Gene Therapy, 9, 778-786.
[112] Chan, T., Sami, A., El-Gayed, A., Guo, X. and Xiang, J. (2006) HER-2/Neu-Gene Engineered Dendritic Cell Vaccine Stimulates Stronger HER-2/Neu-Specific Immune Responses Compared to DNA Vaccination. Gene Therapy, 13, 1391-1402.
[113] Sas, S., Chan, T., Sami, A., El-Gayed, A. and Xiang, J. (2008) Vaccination of Fiber-Modified Adenovirus-Transfected Dendritic Cells to Express HER-2/Neu Stimulates Efficient HER-2/Neu-Specific Humoral and CTL Responses and Reduces Breast Carcinogenesis in Transgenic Mice. Cancer Gene Therapy, 15, 655-666.
[114] Brossart, P., Wirths, S., Stuhler, G., Reichardt, V.L., Kanz, L. and Brugger, W. (2000) Induction of Cytotoxic T-Lymphocyte Responses in Vivo after Vaccinations with Peptide-Pulsed Dendritic Cells. Blood, 96, 3102-3108.
[115] Morse, M.A., Hobeika, A., Osada, T., Niedzwiecki, D., Marcom, P.K., Blackwell, K.L., Anders, C., Devi, G.R., Lyerly, H.K. and Clay, T.M. (2007) Long-Term Disease-Free Survival and T Cell and Antibody Responses in Women with High-Risk HER2+ Breast Cancer Following Vaccination against Her2. Journal of Translational Medicine, 5, 42.
[116] Peethambaram, P.P., Melisko, M.E., Rinn, K.J., Alberts, S.R., Provost, N.M., Jones, L.A., Sims, R.B., Lin, L.R., Frohlich, M.W. and Park, J.W. (2009) A Phase I Trial of Immunotherapy with Lapuleucel-T (APC8024) in Patients with Refractory Metastatic Tumors that Express HER-2/Neu. Clinical Cancer Research, 15, 5937-5944.
[117] Disis, M., Dang, Y., Bates, N., Higgins, D., Childs, J., Slota, M., Coveler, A., Jackson, E., Waisman, J. and Salaza, L. (2010) Phase II Study of a HER-2/Neu (HER2) Intracellular Domain (ICD) Vaccine Given Concurrently with Trastuzumab in Patients with Newly Diagnosed Advanced Stage Breast Cancer. Cancer Research, 69, 5102.
[118] Czerniecki, B.J., Koski, G.K., Koldovsky, U., Xu, S., Cohen, P.A., Mick, R., Nisenbaum, H., Pasha, T., Xu, M., Fox, K.R., Weinstein, S., Orel, S.G., Vonderheide, R., Coukos, G., DeMichele, A., Araujo, L., Spitz, F.R., Rosen, M., Levine, B.L., June, C. and Zhang, P.J. (2007) Targeting HER-2/Neu in Early Breast Cancer Development Using Dendritic Cells with Staged Interleukin-12 Burst Secretion. Cancer Research, 67, 1842-1852.
[119] Disis, M.L., Wallace, D.R., Gooley, T.A., Dang, Y., Slota, M., Lu, H., Coveler, A.L., Childs, J.S., Higgins, D.M., Fintak, P.A., dela Rosa, C., Tietje, K., Link, J., Waisman, J. and Salazar, L.G. (2009) Concurrent Trastuzumab and HER2/Neu-Specific Vaccination in Patients with Metastatic Breast Cancer. Journal of Clinical Oncology, 27, 4685- 4692.
[120] Benavides, L.C., Gates, J.D., Carmichael, M.G., Patil, R., Holmes, J.P., Hueman, M.T., Mittendorf, E.A., Craig, D., Stojadinovic, A., Ponniah, S. and Peoples, G.E. (2009) The Impact of HER2/Neu Expression Level on Response to the E75 Vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clinical Cancer Research, 15, 2895-2904.
[121] Hamilton, E., Blackwell, K., Hobeika, A.C., Clay, T.M., Broadwater, G., Ren, X.R., Chen, W., Castro, H., Lehmann, F., Spector, N., Wei, J., Osada, T. and Lyerly, H.K. (2012) Phase I Clinical Trial of HER2-Specific Immunotherapy with Concomitant HER2 Kinase Inhibition. Journal of Translational Medicine, 10, 28.

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