Cancer and Metastasis Reviews

, Volume 35, Issue 4, pp 525–546 | Cite as

Immunotherapy for breast cancer: past, present, and future

  • Alison Spellman
  • Shou-Ching TangEmail author


Immunotherapy has shown promise in many solid tumors including melanoma and non-small cell lung cancer with an evolving role in breast cancer. Immunotherapy encompasses a wide range of therapies including immune checkpoint inhibition, monoclonal antibodies, bispecific antibodies, vaccinations, antibody-drug conjugates, and identifying other emerging interventions targeting the tumor microenvironment. Increasing efficacy of these treatments in breast cancer patients requires identification of better biomarkers to guide patient selection; recognizing when to initiate these therapies in multi-modality treatment plans; establishing novel assays to monitor immune-mediated responses; and creating combined systemic therapy options incorporating conventional treatments such as chemotherapy and endocrine therapy. This review will focus on the current role and future directions of many of these immunotherapies in breast cancer, as well as highlighting clinical trials that are investigating several of these active issues.


Immunotherapy Breast cancer Review Checkpoint inhibitor Biomarkers Clinical trials 



We thank Ms. Lynsey Ekema and Mr. Aaron Burkhardt from Georgia Regents University Illustration Department as well as Lisa Middleton from Georgia Regents University Cancer Center for their kind help in graphic design and drawing for the figures.


  1. 1.
    Finn, O. J. (2008). Cancer immunology. The New England Journal of Medicine, 358(25), 2704–2715. doi: 10.1056/NEJMra072739.PubMedCrossRefGoogle Scholar
  2. 2.
    Murphy, J. F. (2010). Trends in cancer immunotherapy. Clin Med Insights Oncol, 4, 67–80.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Fisher, R. I., Rosenberg, S. A., & Fyfe, G. (2000). Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. The Cancer Journal from Scientific American, 6(Suppl 1), S55–S57.PubMedGoogle Scholar
  4. 4.
    Eggermont, A. M., Suciu, S., Santinami, M., Testori, A., Kruit, W. H., Marsden, J., et al. (2008). Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet, 372(9633), 117–126. doi: 10.1016/S0140-6736(08)61033-8.PubMedCrossRefGoogle Scholar
  5. 5.
    Fyfe, G., Fisher, R. I., Rosenberg, S. A., Sznol, M., Parkinson, D. R., & Louie, A. C. (1995). Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of Clinical Oncology, 13(3), 688–696.PubMedGoogle Scholar
  6. 6.
    Chavez-Galan, L., Arenas-Del Angel, M. C., Zenteno, E., Chavez, R., & Lascurain, R. (2009). Cell death mechanisms induced by cytotoxic lymphocytes. Cellular & Molecular Immunology, 6(1), 15–25. doi: 10.1038/cmi.2009.3.CrossRefGoogle Scholar
  7. 7.
    Nimmerjahn, F., & Ravetch, J. V. (2008). Fcgamma receptors as regulators of immune responses. Nature Reviews. Immunology, 8(1), 34–47. doi: 10.1038/nri2206.PubMedCrossRefGoogle Scholar
  8. 8.
    Bakema, J. E., & van Egmond, M. (2014). Fc receptor-dependent mechanisms of monoclonal antibody therapy of cancer. Current Topics in Microbiology and Immunology, 382, 373–392. doi: 10.1007/978-3-319-07911-0_17.PubMedGoogle Scholar
  9. 9.
    Chung, S., Lin, Y. L., Reed, C., Ng, C., Cheng, Z. J., Malavasi, F., et al. (2014). Characterization of in vitro antibody-dependent cell-mediated cytotoxicity activity of therapeutic antibodies - impact of effector cells. Journal of Immunological Methods, 407, 63–75. doi: 10.1016/j.jim.2014.03.021.PubMedCrossRefGoogle Scholar
  10. 10.
    Rudd, C. E., Taylor, A., & Schneider, H. (2009). CD28 and CTLA-4 coreceptor expression and signal transduction. Immunological Reviews, 229(1), 12–26. doi: 10.1111/j.1600-065X.2009.00770.x.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 12(4), 252–264. doi: 10.1038/nrc3239.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., et al. (2008). CTLA-4 control over Foxp3+ regulatory T cell function. Science, 322(5899), 271–275. doi: 10.1126/science.1160062.PubMedCrossRefGoogle Scholar
  13. 13.
    Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J., & Allison, J. P. (2009). Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. The Journal of Experimental Medicine, 206(8), 1717–1725. doi: 10.1084/jem.20082492.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., et al. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. The New England Journal of Medicine, 363(8), 711–723. doi: 10.1056/NEJMoa1003466.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Simpson, T. R., Li, F., Montalvo-Ortiz, W., Sepulveda, M. A., Bergerhoff, K., Arce, F., et al. (2013). Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. The Journal of Experimental Medicine, 210(9), 1695–1710. doi: 10.1084/jem.20130579.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bulliard, Y., Jolicoeur, R., Windman, M., Rue, S. M., Ettenberg, S., Knee, D. A., et al. (2013). Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. The Journal of Experimental Medicine, 210(9), 1685–1693. doi: 10.1084/jem.20130573.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Ribas, A., Kefford, R., Marshall, M. A., Punt, C. J., Haanen, J. B., Marmol, M., et al. (2013). Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. Journal of Clinical Oncology, 31(5), 616–622. doi: 10.1200/JCO.2012.44.6112.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Vonderheide, R. H., LoRusso, P. M., Khalil, M., Gartner, E. M., Khaira, D., Soulieres, D., et al. (2010). Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clinical Cancer Research, 16(13), 3485–3494. doi: 10.1158/1078-0432.CCR-10-0505.PubMedCrossRefGoogle Scholar
  19. 19.
    Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008). PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology, 26, 677–704. doi: 10.1146/annurev.immunol.26.021607.090331.PubMedCrossRefGoogle Scholar
  20. 20.
    Fife, B. T., Pauken, K. E., Eagar, T. N., Obu, T., Wu, J., Tang, Q., et al. (2009). Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nature Immunology, 10(11), 1185–1192. doi: 10.1038/ni.1790.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., et al. (2006). Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 439(7077), 682–687. doi: 10.1038/nature04444.PubMedCrossRefGoogle Scholar
  22. 22.
    Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., et al. (2000). Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. The Journal of Experimental Medicine, 192(7), 1027–1034.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Ahmadzadeh, M., Johnson, L. A., Heemskerk, B., Wunderlich, J. R., Dudley, M. E., White, D. E., et al. (2009). Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood, 114(8), 1537–1544. doi: 10.1182/blood-2008-12-195792.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., et al. (2002). Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Medicine, 8(8), 793–800. doi: 10.1038/nm730.PubMedGoogle Scholar
  25. 25.
    Taube, J. M., Anders, R. A., Young, G. D., Xu, H., Sharma, R., McMiller, T. L., et al. (2012). Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Science Translational Medicine, 4(127), 127ra137. doi: 10.1126/scitranslmed.3003689.CrossRefGoogle Scholar
  26. 26.
    Muenst, S., Soysal, S. D., Gao, F., Obermann, E. C., Oertli, D., & Gillanders, W. E. (2013). The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Research and Treatment, 139(3), 667–676. doi: 10.1007/s10549-013-2581-3.PubMedCrossRefGoogle Scholar
  27. 27.
    Ghebeh, H., Mohammed, S., Al-Omair, A., Qattan, A., Lehe, C., Al-Qudaihi, G., et al. (2006). The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia, 8(3), 190–198. doi: 10.1593/neo.05733.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Sabatier, R., Finetti, P., Mamessier, E., Adelaide, J., Chaffanet, M., Ali, H. R., et al. (2015). Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget, 6(7), 5449–5464.PubMedCrossRefGoogle Scholar
  29. 29.
    Mittendorf, E. A., Philips, A. V., Meric-Bernstam, F., Qiao, N., Wu, Y., Harrington, S., et al. (2014). PD-L1 expression in triple-negative breast cancer. Cancer Immunology Research, 2(4), 361–370. doi: 10.1158/2326-6066.CIR-13-0127.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gatalica, Z., Snyder, C., Maney, T., Ghazalpour, A., Holterman, D. A., Xiao, N., et al. (2014). Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiology, Biomarkers & Prevention, 23(12), 2965–2970. doi: 10.1158/1055-9965.EPI-14-0654.CrossRefGoogle Scholar
  31. 31.
    Zhang, P., Su, D. M., Liang, M., & Fu, J. (2008). Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Molecular Immunology, 45(5), 1470–1476. doi: 10.1016/j.molimm.2007.08.013.PubMedCrossRefGoogle Scholar
  32. 32.
    Wimberly, H., Brown, J. R., Schalper, K., Haack, H., Silver, M. R., Nixon, C., et al. (2015). PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy in breast cancer. Cancer Immunology Research, 3(4), 326–332. doi: 10.1158/2326-6066.CIR-14-0133.PubMedCrossRefGoogle Scholar
  33. 33.
    Verbrugge, I., Hagekyriakou, J., Sharp, L. L., Galli, M., West, A., McLaughlin, N. M., et al. (2012). Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Research, 72(13), 3163–3174. doi: 10.1158/0008-5472.CAN-12-0210.PubMedCrossRefGoogle Scholar
  34. 34.
    Ge, Y., Xi, H., Ju, S., & Zhang, X. (2013). Blockade of PD-1/PD-L1 immune checkpoint during DC vaccination induces potent protective immunity against breast cancer in hu-SCID mice. Cancer Letters, 336(2), 253–259. doi: 10.1016/j.canlet.2013.03.010.PubMedCrossRefGoogle Scholar
  35. 35.
    Stagg, J., Loi, S., Divisekera, U., Ngiow, S. F., Duret, H., Yagita, H., et al. (2011). Anti-ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti-PD-1 or anti-CD137 mAb therapy. Proceedings of the National Academy of Sciences of the United States of America, 108(17), 7142–7147. doi: 10.1073/pnas.1016569108.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Gangadhar, T. C., & Vonderheide, R. H. (2014). Mitigating the toxic effects of anticancer immunotherapy. Nature Reviews. Clinical Oncology, 11(2), 91–99. doi: 10.1038/nrclinonc.2013.245.PubMedCrossRefGoogle Scholar
  37. 37.
    Mohit, E., Hashemi, A., & Allahyari, M. (2014). Breast cancer immunotherapy: monoclonal antibodies and peptide-based vaccines. Expert Review of Clinical Immunology, 10(7), 927–961. doi: 10.1586/1744666X.2014.916211.PubMedCrossRefGoogle Scholar
  38. 38.
    Weber, J. S., D'Angelo, S. P., Minor, D., Hodi, F. S., Gutzmer, R., Neyns, B., et al. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology, 16(4), 375–384. doi: 10.1016/S1470-2045(15)70076-8.PubMedCrossRefGoogle Scholar
  39. 39.
    Brahmer, J., Reckamp, K. L., Baas, P., Crino, L., Eberhardt, W. E., Poddubskaya, E., et al. (2015). Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. The New England Journal of Medicine, 373(2), 123–135. doi: 10.1056/NEJMoa1504627.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Motzer, R. J., Escudier, B., McDermott, D. F., George, S., Hammers, H. J., Srinivas, S., et al. (2015). Nivolumab versus everolimus in advanced renal-cell carcinoma. The New England Journal of Medicine, 373(19), 1803–1813. doi: 10.1056/NEJMoa1510665.PubMedCrossRefGoogle Scholar
  41. 41.
    Robert, C., Ribas, A., Wolchok, J. D., Hodi, F. S., Hamid, O., Kefford, R., et al. (2014). Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet, 384(9948), 1109–1117. doi: 10.1016/S0140-6736(14)60958-2.PubMedCrossRefGoogle Scholar
  42. 42.
    Garon, E. B., Rizvi, N. A., Hui, R., Leighl, N., Balmanoukian, A. S., Eder, J. P., et al. (2015). Pembrolizumab for the treatment of non-small-cell lung cancer. The New England Journal of Medicine, 372(21), 2018–2028. doi: 10.1056/NEJMoa1501824.PubMedCrossRefGoogle Scholar
  43. 43.
    Nanda, R., Chow, L. Q., Dees, E. C., Berger, R., Gupta, S., Geva, R., et al. (2015). Abstract S1-09: A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Cancer Res, 75(9 Supplement), S1-09-S01-09.Google Scholar
  44. 44.
    Rugo, H., Delord, J., Im, S., Ott, P., Piha-Paul, S., Bedard, P., et al. (2016). Abstract S5-07: Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor-positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. Cancer Res, 76(4 Supplement), S5-07-S05-07.Google Scholar
  45. 45.
    Cimino-Mathews, A., Foote, J. B., & Emens, L. A. (2015). Immune targeting in breast cancer. Oncology (Williston Park), 29(5), 375–385.Google Scholar
  46. 46.
    Emens, L. A., Braiteh, F. S., Cassier, P., DeLord, J.-P., Eder, J. P., Shen, X., et al. (2015). Abstract PD1-6: Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Cancer Res, 75(9 Supplement), PD1-6-PD1-6.Google Scholar
  47. 47.
    Adams S, D. J., Hamilton E, et al. (December 8–12, 2015). Safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Presented at: San Antonio Breast Cancer Symposium; San Antonio, TX.Google Scholar
  48. 48.
    Dirix, L., Takacs, I., Nikolinakos, P., Jerusalem, G., Arkenau, H., Hamilton, E., et al. (2016). Abstract S1-04: Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Cancer Res, 76(4 Supplement), S1-04-S01-04.Google Scholar
  49. 49.
    Emens, L. A. (2012). Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade. Expert Review of Anticancer Therapy, 12(12), 1597–1611. doi: 10.1586/era.12.147.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Denkert, C., Loibl, S., Noske, A., Roller, M., Muller, B. M., Komor, M., et al. (2010). Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. Journal of Clinical Oncology, 28(1), 105–113. doi: 10.1200/JCO.2009.23.7370.PubMedCrossRefGoogle Scholar
  51. 51.
    West, N. R., Milne, K., Truong, P. T., Macpherson, N., Nelson, B. H., & Watson, P. H. (2011). Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Research, 13(6), R126. doi: 10.1186/bcr3072.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Ladoire, S., Mignot, G., Dabakuyo, S., Arnould, L., Apetoh, L., Rebe, C., et al. (2011). In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. The Journal of Pathology, 224(3), 389–400. doi: 10.1002/path.2866.PubMedCrossRefGoogle Scholar
  53. 53.
    Shevach, E. M. (2011). Biological functions of regulatory T cells. Advances in Immunology, 112, 137–176. doi: 10.1016/B978-0-12-387827-4.00004-8.PubMedCrossRefGoogle Scholar
  54. 54.
    Jiang, X. (2014). Harnessing the immune system for the treatment of breast cancer. Journal of Zhejiang University. Science. B, 15(1), 1–15. doi: 10.1631/jzus.B1300264.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bates, G. J., Fox, S. B., Han, C., Leek, R. D., Garcia, J. F., Harris, A. L., et al. (2006). Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. Journal of Clinical Oncology, 24(34), 5373–5380. doi: 10.1200/JCO.2006.05.9584.PubMedCrossRefGoogle Scholar
  56. 56.
    Bohling, S. D., & Allison, K. H. (2008). Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Modern Pathology, 21(12), 1527–1532. doi: 10.1038/modpathol.2008.160.PubMedCrossRefGoogle Scholar
  57. 57.
    Gobert, M., Treilleux, I., Bendriss-Vermare, N., Bachelot, T., Goddard-Leon, S., Arfi, V., et al. (2009). Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Research, 69(5), 2000–2009. doi: 10.1158/0008-5472.CAN-08-2360.PubMedCrossRefGoogle Scholar
  58. 58.
    Olkhanud, P. B., Damdinsuren, B., Bodogai, M., Gress, R. E., Sen, R., Wejksza, K., et al. (2011). Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells. Cancer Research, 71(10), 3505–3515. doi: 10.1158/0008-5472.CAN-10-4316.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Joffroy, C. M., Buck, M. B., Stope, M. B., Popp, S. L., Pfizenmaier, K., & Knabbe, C. (2010). Antiestrogens induce transforming growth factor beta-mediated immunosuppression in breast cancer. Cancer Research, 70(4), 1314–1322. doi: 10.1158/0008-5472.CAN-09-3292.PubMedCrossRefGoogle Scholar
  60. 60.
    Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A., Powell Jr., D. J., et al. (2012). CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Science Translational Medicine, 4(134), 134ra162. doi: 10.1126/scitranslmed.3003330.CrossRefGoogle Scholar
  61. 61.
    Weiss, V. L., Lee, T. H., Song, H., Kouo, T. S., Black, C. M., Sgouros, G., et al. (2012). Trafficking of high avidity HER-2/neu-specific T cells into HER-2/neu-expressing tumors after depletion of effector/memory-like regulatory T cells. PloS One, 7(2), e31962. doi: 10.1371/journal.pone.0031962.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Ni, X., Langridge, T., & Duvic, M. (2015). Depletion of regulatory T cells by targeting CC chemokine receptor type 4 with mogamulizumab. Oncoimmunology, 4(7), e1011524. doi: 10.1080/2162402X.2015.1011524.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Gabrilovich, D. I., & Nagaraj, S. (2009). Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews. Immunology, 9(3), 162–174. doi: 10.1038/nri2506.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Markowitz, J., Wesolowski, R., Papenfuss, T., Brooks, T. R., & Carson 3rd, W. E. (2013). Myeloid-derived suppressor cells in breast cancer. Breast Cancer Research and Treatment, 140(1), 13–21. doi: 10.1007/s10549-013-2618-7.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Diaz-Montero, C. M., Salem, M. L., Nishimura, M. I., Garrett-Mayer, E., Cole, D. J., & Montero, A. J. (2009). Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunology, Immunotherapy, 58(1), 49–59. doi: 10.1007/s00262-008-0523-4.PubMedCrossRefGoogle Scholar
  66. 66.
    Sinha, P., Clements, V. K., & Ostrand-Rosenberg, S. (2005). Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. Journal of Immunology, 174(2), 636–645.CrossRefGoogle Scholar
  67. 67.
    Morales, J. K., Kmieciak, M., Graham, L., Feldmesser, M., Bear, H. D., & Manjili, M. H. (2009). Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells. Cancer Immunology, Immunotherapy, 58(6), 941–953. doi: 10.1007/s00262-008-0609-z.PubMedCrossRefGoogle Scholar
  68. 68.
    Steding, C. E., Wu, S. T., Zhang, Y., Jeng, M. H., Elzey, B. D., & Kao, C. (2011). The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology, 133(2), 221–238. doi: 10.1111/j.1365-2567.2011.03429.x.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Thakur, A., Schalk, D., Sarkar, S. H., Al-Khadimi, Z., Sarkar, F. H., & Lum, L. G. (2012). A Th1 cytokine-enriched microenvironment enhances tumor killing by activated T cells armed with bispecific antibodies and inhibits the development of myeloid-derived suppressor cells. Cancer Immunology, Immunotherapy, 61(4), 497–509. doi: 10.1007/s00262-011-1116-1.PubMedCrossRefGoogle Scholar
  70. 70.
    Montero, A. J., Diaz-Montero, C. M., Deutsch, Y. E., Hurley, J., Koniaris, L. G., Rumboldt, T., et al. (2012). Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer. Breast Cancer Research and Treatment, 132(1), 215–223. doi: 10.1007/s10549-011-1889-0.PubMedCrossRefGoogle Scholar
  71. 71.
    Godin-Ethier, J., Hanafi, L. A., Piccirillo, C. A., & Lapointe, R. (2011). Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clinical Cancer Research, 17(22), 6985–6991. doi: 10.1158/1078-0432.CCR-11-1331.PubMedCrossRefGoogle Scholar
  72. 72.
    Munder, M. (2009). Arginase: an emerging key player in the mammalian immune system. British Journal of Pharmacology, 158(3), 638–651. doi: 10.1111/j.1476-5381.2009.00291.x.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Isla Larrain, M. T., Rabassa, M. E., Lacunza, E., Barbera, A., Creton, A., Segal-Eiras, A., et al. (2014). IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis. Tumour Biology, 35(7), 6511–6519. doi: 10.1007/s13277-014-1859-3.PubMedCrossRefGoogle Scholar
  74. 74.
    Li, R., Wei, F., Yu, J., Li, H., Ren, X., & Hao, X. (2009). IDO inhibits T-cell function through suppressing Vav1 expression and activation. Cancer Biology & Therapy, 8(14), 1402–1408.CrossRefGoogle Scholar
  75. 75.
    Sun, J., Yu, J., Li, H., Yang, L., Wei, F., Yu, W., et al. (2011). Upregulated expression of indoleamine 2, 3-dioxygenase in CHO cells induces apoptosis of competent T cells and increases proportion of Treg cells. Journal of Experimental & Clinical Cancer Research, 30, 82. doi: 10.1186/1756-9966-30-82.CrossRefGoogle Scholar
  76. 76.
    Munn, D. H., & Mellor, A. L. (2007). Indoleamine 2,3-dioxygenase and tumor-induced tolerance. The Journal of Clinical Investigation, 117(5), 1147–1154. doi: 10.1172/JCI31178.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Yu, J., Du, W., Yan, F., Wang, Y., Li, H., Cao, S., et al. (2013). Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. Journal of Immunology, 190(7), 3783–3797. doi: 10.4049/jimmunol.1201449.CrossRefGoogle Scholar
  78. 78.
    Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E., & Prendergast, G. C. (2005). Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Medicine, 11(3), 312–319. doi: 10.1038/nm1196.PubMedCrossRefGoogle Scholar
  79. 79.
    Soliman, H. H., Jackson, E., Neuger, T., Dees, E. C., Harvey, R. D., Han, H., et al. (2014). A first in man phase I trial of the oral immunomodulator, indoximod, combined with docetaxel in patients with metastatic solid tumors. Oncotarget, 5(18), 8136–8146.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Tang, S., Montero, A., Munn, D., Link, C., Vahanian, N., Kennedy, E., et al. (2016). Abstract P2-11-09: A phase 2 randomized trial of the IDO pathway inhibitor indoximod in combination with taxane based chemotherapy for metastatic breast cancer: Preliminary data. Cancer Res, 76(4 Supplement), P2-11-09-P12-11-09.Google Scholar
  81. 81.
    Qian, B. Z., & Pollard, J. W. (2010). Macrophage diversity enhances tumor progression and metastasis. Cell, 141(1), 39–51. doi: 10.1016/j.cell.2010.03.014.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Laoui, D., Movahedi, K., Van Overmeire, E., Van den Bossche, J., Schouppe, E., Mommer, C., et al. (2011). Tumor-associated macrophages in breast cancer: distinct subsets, distinct functions. The International Journal of Developmental Biology, 55(7–9), 861–867. doi: 10.1387/ijdb.113371dl.PubMedCrossRefGoogle Scholar
  83. 83.
    Obeid, E., Nanda, R., Fu, Y. X., & Olopade, O. I. (2013). The role of tumor-associated macrophages in breast cancer progression (review). International Journal of Oncology, 43(1), 5–12. doi: 10.3892/ijo.2013.1938.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Tang, X. (2013). Tumor-associated macrophages as potential diagnostic and prognostic biomarkers in breast cancer. Cancer Letters, 332(1), 3–10. doi: 10.1016/j.canlet.2013.01.024.PubMedCrossRefGoogle Scholar
  85. 85.
    Leek, R. D., Lewis, C. E., Whitehouse, R., Greenall, M., Clarke, J., & Harris, A. L. (1996). Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Research, 56(20), 4625–4629.PubMedGoogle Scholar
  86. 86.
    Tsutsui, S., Yasuda, K., Suzuki, K., Tahara, K., Higashi, H., & Era, S. (2005). Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncology Reports, 14(2), 425–431.PubMedGoogle Scholar
  87. 87.
    Mahmoud, S. M., Lee, A. H., Paish, E. C., Macmillan, R. D., Ellis, I. O., & Green, A. R. (2012). Tumour-infiltrating macrophages and clinical outcome in breast cancer. Journal of Clinical Pathology, 65(2), 159–163. doi: 10.1136/jclinpath-2011-200355.PubMedCrossRefGoogle Scholar
  88. 88.
    Campbell, M. J., Tonlaar, N. Y., Garwood, E. R., Huo, D., Moore, D. H., Khramtsov, A. I., et al. (2011). Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. Breast Cancer Research and Treatment, 128(3), 703–711. doi: 10.1007/s10549-010-1154-y.PubMedCrossRefGoogle Scholar
  89. 89.
    Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454(7203), 436–444. doi: 10.1038/nature07205.PubMedCrossRefGoogle Scholar
  90. 90.
    Biswas, S. K., & Mantovani, A. (2010). Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunology, 11(10), 889–896. doi: 10.1038/ni.1937.PubMedCrossRefGoogle Scholar
  91. 91.
    Ruffell, B., Affara, N. I., & Coussens, L. M. (2012). Differential macrophage programming in the tumor microenvironment. Trends in Immunology, 33(3), 119–126. doi: 10.1016/ Scholar
  92. 92.
    Huang, Y., Yuan, J., Righi, E., Kamoun, W. S., Ancukiewicz, M., Nezivar, J., et al. (2012). Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proceedings of the National Academy of Sciences of the United States of America, 109(43), 17561–17566. doi: 10.1073/pnas.1215397109.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Zhang, X., Tian, W., Cai, X., Wang, X., Dang, W., Tang, H., et al. (2013). Hydrazinocurcumin Encapsuled nanoparticles "re-educate" tumor-associated macrophages and exhibit anti-tumor effects on breast cancer following STAT3 suppression. PloS One, 8(6), e65896. doi: 10.1371/journal.pone.0065896.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    DeNardo, D. G., Brennan, D. J., Rexhepaj, E., Ruffell, B., Shiao, S. L., Madden, S. F., et al. (2011). Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discovery, 1(1), 54–67. doi: 10.1158/2159-8274.CD-10-0028.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Leek, R. D., Hunt, N. C., Landers, R. J., Lewis, C. E., Royds, J. A., & Harris, A. L. (2000). Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. The Journal of Pathology, 190(4), 430–436. doi: 10.1002/(SICI)1096-9896(200003)190:4<430::AID-PATH538>3.0.CO;2-6.PubMedCrossRefGoogle Scholar
  96. 96.
    Lewis, J. S., Landers, R. J., Underwood, J. C., Harris, A. L., & Lewis, C. E. (2000). Expression of vascular endothelial growth factor by macrophages is up-regulated in poorly vascularized areas of breast carcinomas. The Journal of Pathology, 192(2), 150–158. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH687>3.0.CO;2-G.PubMedCrossRefGoogle Scholar
  97. 97.
    Dirkx, A. E., Oude Egbrink, M. G., Wagstaff, J., & Griffioen, A. W. (2006). Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. Journal of Leukocyte Biology, 80(6), 1183–1196. doi: 10.1189/jlb.0905495.PubMedCrossRefGoogle Scholar
  98. 98.
    Kakarala, M., & Wicha, M. S. (2008). Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. Journal of Clinical Oncology, 26(17), 2813–2820. doi: 10.1200/JCO.2008.16.3931.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Korkaya, H., Liu, S., & Wicha, M. S. (2011). Breast cancer stem cells, cytokine networks, and the tumor microenvironment. The Journal of Clinical Investigation, 121(10), 3804–3809. doi: 10.1172/JCI57099.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Yang, J., Liao, D., Chen, C., Liu, Y., Chuang, T. H., Xiang, R., et al. (2013). Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells, 31(2), 248–258. doi: 10.1002/stem.1281.PubMedCrossRefGoogle Scholar
  101. 101.
    Ding, J., Jin, W., Chen, C., Shao, Z., & Wu, J. (2012). Tumor associated macrophage x cancer cell hybrids may acquire cancer stem cell properties in breast cancer. PloS One, 7(7), e41942. doi: 10.1371/journal.pone.0041942.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Iliopoulos, D., Hirsch, H. A., & Struhl, K. (2009). An epigenetic switch involving NF-kappaB, Lin28, let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell, 139(4), 693–706. doi: 10.1016/j.cell.2009.10.014.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Salgado, R., Junius, S., Benoy, I., Van Dam, P., Vermeulen, P., Van Marck, E., et al. (2003). Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. International Journal of Cancer, 103(5), 642–646. doi: 10.1002/ijc.10833.PubMedCrossRefGoogle Scholar
  104. 104.
    Dethlefsen, C., Hojfeldt, G., & Hojman, P. (2013). The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Research and Treatment, 138(3), 657–664. doi: 10.1007/s10549-013-2488-z.PubMedCrossRefGoogle Scholar
  105. 105.
    Todorovic-Rakovic, N., & Milovanovic, J. (2013). Interleukin-8 in breast cancer progression. Journal of Interferon & Cytokine Research, 33(10), 563–570. doi: 10.1089/jir.2013.0023.CrossRefGoogle Scholar
  106. 106.
    Marotta, L. L., Almendro, V., Marusyk, A., Shipitsin, M., Schemme, J., Walker, S. R., et al. (2011). The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(−) stem cell-like breast cancer cells in human tumors. The Journal of Clinical Investigation, 121(7), 2723–2735. doi: 10.1172/JCI44745.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Charafe-Jauffret, E., Ginestier, C., Iovino, F., Wicinski, J., Cervera, N., Finetti, P., et al. (2009). Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Research, 69(4), 1302–1313. doi: 10.1158/0008-5472.CAN-08-2741.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Hartman, Z. C., Poage, G. M., den Hollander, P., Tsimelzon, A., Hill, J., Panupinthu, N., et al. (2013). Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Research, 73(11), 3470–3480. doi: 10.1158/0008-5472.CAN-12-4524-T.PubMedCrossRefGoogle Scholar
  109. 109.
    Xie, G., Yao, Q., Liu, Y., Du, S., Liu, A., Guo, Z., et al. (2012). IL-6-induced epithelial-mesenchymal transition promotes the generation of breast cancer stem-like cells analogous to mammosphere cultures. International Journal of Oncology, 40(4), 1171–1179. doi: 10.3892/ijo.2011.1275.PubMedGoogle Scholar
  110. 110.
    Hwang, M. S., Yu, N., Stinson, S. Y., Yue, P., Newman, R. J., Allan, B. B., et al. (2013). miR-221/222 targets adiponectin receptor 1 to promote the epithelial-to-mesenchymal transition in breast cancer. PLoS One, 8(6), e66502, doi:10.1371/journal.pone.0066502.Google Scholar
  111. 111.
    Britschgi, A., Andraos, R., Brinkhaus, H., Klebba, I., Romanet, V., Muller, U., et al. (2012). JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell, 22(6), 796–811. doi: 10.1016/j.ccr.2012.10.023.PubMedCrossRefGoogle Scholar
  112. 112.
    Ahn, E. R., & Vogel, C. L. (2012). Dual HER2-targeted approaches in HER2-positive breast cancer. Breast Cancer Research and Treatment, 131(2), 371–383. doi: 10.1007/s10549-011-1781-y.PubMedCrossRefGoogle Scholar
  113. 113.
    Buzdar, A. U., Ibrahim, N. K., Francis, D., Booser, D. J., Thomas, E. S., Theriault, R. L., et al. (2005). Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. Journal of Clinical Oncology, 23(16), 3676–3685. doi: 10.1200/JCO.2005.07.032.PubMedCrossRefGoogle Scholar
  114. 114.
    Gianni, L., Eiermann, W., Semiglazov, V., Manikhas, A., Lluch, A., Tjulandin, S., et al. (2010). Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet, 375(9712), 377–384. doi: 10.1016/S0140-6736(09)61964-4.PubMedCrossRefGoogle Scholar
  115. 115.
    Yin, W., Jiang, Y., Shen, Z., Shao, Z., & Lu, J. (2011). Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer patients: a meta-analysis of published randomized controlled trials. PloS One, 6(6), e21030. doi: 10.1371/journal.pone.0021030.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Gianni, L., Dafni, U., Gelber, R. D., Azambuja, E., Muehlbauer, S., Goldhirsch, A., et al. (2011). Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. The Lancet Oncology, 12(3), 236–244. doi: 10.1016/S1470-2045(11)70033-X.PubMedCrossRefGoogle Scholar
  117. 117.
    Fang, L., Barekati, Z., Zhang, B., Liu, Z., & Zhong, X. (2011). Targeted therapy in breast cancer: what's new? Swiss Medical Weekly, 141, w13231. doi: 10.4414/smw.2011.13231.PubMedGoogle Scholar
  118. 118.
    Huang, Y., Fu, P., & Fan, W. (2013). Novel targeted therapies to overcome trastuzumab resistance in HER2-overexpressing metastatic breast cancer. Current Drug Targets, 14(8), 889–898.PubMedCrossRefGoogle Scholar
  119. 119.
    Nahta, R., Hung, M. C., & Esteva, F. J. (2004). The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Research, 64(7), 2343–2346.PubMedCrossRefGoogle Scholar
  120. 120.
    Agus, D. B., Akita, R. W., Fox, W. D., Lewis, G. D., Higgins, B., Pisacane, P. I., et al. (2002). Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell, 2(2), 127–137.PubMedCrossRefGoogle Scholar
  121. 121.
    Franklin, M. C., Carey, K. D., Vajdos, F. F., Leahy, D. J., de Vos, A. M., & Sliwkowski, M. X. (2004). Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell, 5(4), 317–328.PubMedCrossRefGoogle Scholar
  122. 122.
    Scheuer, W., Friess, T., Burtscher, H., Bossenmaier, B., Endl, J., & Hasmann, M. (2009). Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Research, 69(24), 9330–9336. doi: 10.1158/0008-5472.CAN-08-4597.PubMedCrossRefGoogle Scholar
  123. 123.
    Capelan, M., Pugliano, L., De Azambuja, E., Bozovic, I., Saini, K. S., Sotiriou, C., et al. (2013). Pertuzumab: new hope for patients with HER2-positive breast cancer. Annals of Oncology, 24(2), 273–282. doi: 10.1093/annonc/mds328.PubMedCrossRefGoogle Scholar
  124. 124.
    Swain, S. M., Kim, S. B., Cortes, J., Ro, J., Semiglazov, V., Campone, M., et al. (2013). Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. The Lancet Oncology, 14(6), 461–471. doi: 10.1016/S1470-2045(13)70130-X.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Gianni, L., Pienkowski, T., Im, Y. H., Roman, L., Tseng, L. M., Liu, M. C., et al. (2012). Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The Lancet Oncology, 13(1), 25–32. doi: 10.1016/S1470-2045(11)70336-9.PubMedCrossRefGoogle Scholar
  126. 126.
    Scott, A. M., Wolchok, J. D., & Old, L. J. (2012). Antibody therapy of cancer. Nature Reviews. Cancer, 12(4), 278–287. doi: 10.1038/nrc3236.PubMedCrossRefGoogle Scholar
  127. 127.
    Musolino, A., Naldi, N., Bortesi, B., Pezzuolo, D., Capelletti, M., Missale, G., et al. (2008). Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. Journal of Clinical Oncology, 26(11), 1789–1796. doi: 10.1200/JCO.2007.14.8957.PubMedCrossRefGoogle Scholar
  128. 128.
    Mellor, J. D., Brown, M. P., Irving, H. R., Zalcberg, J. R., & Dobrovic, A. (2013). A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. Journal of Hematology & Oncology, 6, 1. doi: 10.1186/1756-8722-6-1.CrossRefGoogle Scholar
  129. 129.
    Lameris, R., de Bruin, R. C., Schneiders, F. L., van Bergen en Henegouwen, P. M., Verheul, H. M., de Gruijl, T. D., et al. (2014). Bispecific antibody platforms for cancer immunotherapy. Critical Reviews in Oncology/Hematology, 92(3), 153–165. doi: 10.1016/j.critrevonc.2014.08.003.PubMedCrossRefGoogle Scholar
  130. 130.
    Holliger, P., & Hudson, P. J. (2005). Engineered antibody fragments and the rise of single domains. Nature Biotechnology, 23(9), 1126–1136. doi: 10.1038/nbt1142.PubMedCrossRefGoogle Scholar
  131. 131.
    Chames, P., Van Regenmortel, M., Weiss, E., & Baty, D. (2009). Therapeutic antibodies: successes, limitations and hopes for the future. British Journal of Pharmacology, 157(2), 220–233. doi: 10.1111/j.1476-5381.2009.00190.x.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Vaughan, A. T., Iriyama, C., Beers, S. A., Chan, C. H., Lim, S. H., Williams, E. L., et al. (2014). Inhibitory FcgammaRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity. Blood, 123(5), 669–677. doi: 10.1182/blood-2013-04-490821.PubMedCrossRefGoogle Scholar
  133. 133.
    Schaefer, G., Haber, L., Crocker, L. M., Shia, S., Shao, L., Dowbenko, D., et al. (2011). A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell, 20(4), 472–486. doi: 10.1016/j.ccr.2011.09.003.PubMedCrossRefGoogle Scholar
  134. 134.
    Bostrom, J., Yu, S. F., Kan, D., Appleton, B. A., Lee, C. V., Billeci, K., et al. (2009). Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science, 323(5921), 1610–1614. doi: 10.1126/science.1165480.PubMedCrossRefGoogle Scholar
  135. 135.
    Robinson, M. K., Hodge, K. M., Horak, E., Sundberg, A. L., Russeva, M., Shaller, C. C., et al. (2008). Targeting ErbB2 and ErbB3 with a bispecific single-chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. British Journal of Cancer, 99(9), 1415–1425. doi: 10.1038/sj.bjc.6604700.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    McDonagh, C. F., Huhalov, A., Harms, B. D., Adams, S., Paragas, V., Oyama, S., et al. (2012). Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Molecular Cancer Therapeutics, 11(3), 582–593. doi: 10.1158/1535-7163.MCT-11-0820.PubMedCrossRefGoogle Scholar
  137. 137.
    Oyama, S. K., Paragas, V., Adams, S., Luus, L., Huhalov, A., Kudla, A. J., et al. (2011). MM-111, an ErbB2/ErbB3 bispecific antibody, effectively combines with lapatinib to inhibit growth of ErbB2-overexpressing tumor cells. Cancer Research, 71(8 Supplement), 654.CrossRefGoogle Scholar
  138. 138.
    May, C., Sapra, P., & Gerber, H. P. (2012). Advances in bispecific biotherapeutics for the treatment of cancer. Biochemical Pharmacology, 84(9), 1105–1112. doi: 10.1016/j.bcp.2012.07.011.PubMedCrossRefGoogle Scholar
  139. 139.
    Heiss, M. M., Murawa, P., Koralewski, P., Kutarska, E., Kolesnik, O. O., Ivanchenko, V. V., et al. (2010). The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. International Journal of Cancer, 127(9), 2209–2221. doi: 10.1002/ijc.25423.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Jager, M., Schoberth, A., Ruf, P., Hess, J., & Lindhofer, H. (2009). The trifunctional antibody ertumaxomab destroys tumor cells that express low levels of human epidermal growth factor receptor 2. Cancer Research, 69(10), 4270–4276. doi: 10.1158/0008-5472.CAN-08-2861.PubMedCrossRefGoogle Scholar
  141. 141.
    Topp, M. S., Gokbuget, N., Stein, A. S., Zugmaier, G., O'Brien, S., Bargou, R. C., et al. (2015). Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. The Lancet Oncology, 16(1), 57–66. doi: 10.1016/S1470-2045(14)71170-2.PubMedCrossRefGoogle Scholar
  142. 142.
    Junttila, T. T., Li, J., Johnston, J., Hristopoulos, M., Clark, R., Ellerman, D., et al. (2014). Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells. Cancer Research, 74(19), 5561–5571. doi: 10.1158/0008-5472.CAN-13-3622-T.PubMedCrossRefGoogle Scholar
  143. 143.
    Arteaga, C. L., Sliwkowski, M. X., Osborne, C. K., Perez, E. A., Puglisi, F., & Gianni, L. (2012). Treatment of HER2-positive breast cancer: current status and future perspectives. Nature Reviews. Clinical Oncology, 9(1), 16–32. doi: 10.1038/nrclinonc.2011.177.CrossRefGoogle Scholar
  144. 144.
    Tsang, R. Y., & Finn, R. S. (2012). Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. British Journal of Cancer, 106(1), 6–13. doi: 10.1038/bjc.2011.516.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Verma, S., Miles, D., Gianni, L., Krop, I. E., Welslau, M., Baselga, J., et al. (2012). Trastuzumab emtansine for HER2-positive advanced breast cancer. The New England Journal of Medicine, 367(19), 1783–1791. doi: 10.1056/NEJMoa1209124.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Krop, I. E., Beeram, M., Modi, S., Jones, S. F., Holden, S. N., Yu, W., et al. (2010). Phase I study of trastuzumab-DM1, an HER2 antibody-drug conjugate, given every 3 weeks to patients with HER2-positive metastatic breast cancer. Journal of Clinical Oncology, 28(16), 2698–2704. doi: 10.1200/JCO.2009.26.2071.PubMedCrossRefGoogle Scholar
  147. 147.
    Krop, I. E., LoRusso, P., Miller, K. D., Modi, S., Yardley, D., Rodriguez, G., et al. (2012). A phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. Journal of Clinical Oncology, 30(26), 3234–3241. doi: 10.1200/JCO.2011.40.5902.PubMedCrossRefGoogle Scholar
  148. 148.
    Burris 3rd, H. A., Rugo, H. S., Vukelja, S. J., Vogel, C. L., Borson, R. A., Limentani, S., et al. (2011). Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. Journal of Clinical Oncology, 29(4), 398–405. doi: 10.1200/JCO.2010.29.5865.PubMedCrossRefGoogle Scholar
  149. 149.
    Boyraz, B., Sendur, M. A., Aksoy, S., Babacan, T., Roach, E. C., Kizilarslanoglu, M. C., et al. (2013). Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Current Medical Research and Opinion, 29(4), 405–414. doi: 10.1185/03007995.2013.775113.PubMedCrossRefGoogle Scholar
  150. 150.
    Krop, I. E., Kim, S. B., Gonzalez-Martin, A., LoRusso, P. M., Ferrero, J. M., Smitt, M., et al. (2014). Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. The Lancet Oncology, 15(7), 689–699. doi: 10.1016/S1470-2045(14)70178-0.PubMedCrossRefGoogle Scholar
  151. 151.
    Ellis, P. A., Barrios, C. H., Eiermann, W., Toi, M., Im, Y.-H., Conte, P. F., et al. Phase III, randomized study of trastuzumab emtansine (T-DM1){+/−} pertuzumab (P) vs trastuzumab+ taxane (HT) for first-line treatment of HER2-positive MBC: Primary results from the MARIANNE study. In ASCO Annual Meeting Proceedings, 2015 (Vol. 33, pp. 507, Vol. 15_suppl)Google Scholar
  152. 152.
    LoRusso, P. (2015). MM-302 shows clinical activity, tolerability in heavily-pretreated HER2+ breast cancer
  153. 153.
    Wiedermann, U., Davis, A. B., & 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), 1–12. doi: 10.1007/s10549-013-2410-8.PubMedCrossRefGoogle Scholar
  154. 154.
    Wortzel, R. D., Philipps, C., & Schreiber, H. (1983). Multiple tumour-specific antigens expressed on a single tumour cell. Nature, 304(5922), 165–167.PubMedCrossRefGoogle Scholar
  155. 155.
    Barrow, C., Browning, J., MacGregor, D., Davis, I. D., Sturrock, S., Jungbluth, A. A., et al. (2006). Tumor antigen expression in melanoma varies according to antigen and stage. Clinical Cancer Research, 12(3 Pt 1), 764–771. doi: 10.1158/1078-0432.CCR-05-1544.PubMedCrossRefGoogle Scholar
  156. 156.
    Holmes, J. P., Gates, J. D., Benavides, L. C., Hueman, M. T., Carmichael, M. G., Patil, R., et al. (2008). Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer, 113(7), 1666–1675. doi: 10.1002/cncr.23772.PubMedCrossRefGoogle Scholar
  157. 157.
    Peoples, G. E., Holmes, J. P., Hueman, M. T., Mittendorf, E. A., Amin, A., Khoo, S., et al. (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(3), 797–803. doi: 10.1158/1078-0432.CCR-07-1448.PubMedCrossRefGoogle Scholar
  158. 158.
    Ladjemi, M. Z., Jacot, W., Chardes, T., Pelegrin, A., & Navarro-Teulon, I. (2010). Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunology, Immunotherapy, 59(9), 1295–1312. doi: 10.1007/s00262-010-0869-2.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Hueman, M. T., Stojadinovic, A., Storrer, C. E., Foley, R. J., Gurney, J. M., Shriver, C. D., et al. (2006). Levels of circulating regulatory CD4+CD25+ T cells are decreased in breast cancer patients after vaccination with a HER2/neu peptide (E75) and GM-CSF vaccine. Breast Cancer Research and Treatment, 98(1), 17–29. doi: 10.1007/s10549-005-9108-5.PubMedCrossRefGoogle Scholar
  160. 160.
    Hueman, M. T., Stojadinovic, A., Storrer, C. E., Dehqanzada, Z. A., Gurney, J. M., Shriver, C. D., et al. (2007). Analysis of naive and memory CD4 and CD8 T cell populations in breast cancer patients receiving a HER2/neu peptide (E75) and GM-CSF vaccine. Cancer Immunology, Immunotherapy, 56(2), 135–146. doi: 10.1007/s00262-006-0188-9.PubMedCrossRefGoogle Scholar
  161. 161.
    Holmes, J. P., Clifton, G. T., Patil, R., Benavides, L. C., Gates, J. D., Stojadinovic, A., et al. (2011). Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer, 117(3), 463–471. doi: 10.1002/cncr.25586.PubMedCrossRefGoogle Scholar
  162. 162.
    Mittendorf, E. A., Clifton, G. T., Holmes, J. P., Clive, K. S., Patil, R., Benavides, L. C., 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(10), 2594–2602. doi: 10.1002/cncr.26574.PubMedCrossRefGoogle Scholar
  163. 163.
    Vreeland, T. J., Clifton, G. T., Hale, D. F., Sears, A., Patil, R., Holmes, J., et al. (2012). Abstract P5-16-02: Final results of the phase I/II trials of the E75 adjuvant breast cancer vaccine. Cancer Res, 72(24 Supplement), P5-16-02-P15-16-02.Google Scholar
  164. 164.
    Mittendorf, E. A., Clifton, G. T., Holmes, J. P., Schneble, E., van Echo, D., Ponniah, S., 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. Annals of Oncology, 25(9), 1735–1742. doi: 10.1093/annonc/mdu211.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Carmichael, M. G., Benavides, L. C., Holmes, J. P., Gates, J. D., Mittendorf, E. A., Ponniah, S., 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(2), 292–301. doi: 10.1002/cncr.24756.PubMedCrossRefGoogle Scholar
  166. 166.
    Trappey, F., Berry, J. S., Vreeland, T. J., Hale, D. F., Sears, A. K., Ponniah, S., et al. 2013 Randomized phase II clinical trial of the anti-HER2 (GP2) vaccine to prevent recurrence in high-risk breast cancer patients: a planned interim analysis. In JOURNAL OF CLINICAL ONCOLOGY, (Vol. 31, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  167. 167.
    Clive, K. S., Tyler, J. A., Clifton, G. T., Holmes, J. P., Ponniah, S., Peoples, G. E., et al. (2012). The GP2 peptide: a HER2/neu-based breast cancer vaccine. Journal of Surgical Oncology, 105(5), 452–458. doi: 10.1002/jso.21723.PubMedCrossRefGoogle Scholar
  168. 168.
    Sotiriadou, N. N., Kallinteris, N. L., Gritzapis, A. D., Voutsas, I. F., Papamichail, M., von Hofe, E., et al. (2007). Ii-Key/HER-2/neu(776-790) hybrid peptides induce more effective immunological responses over the native peptide in lymphocyte cultures from patients with HER-2/neu+ tumors. Cancer Immunology, Immunotherapy, 56(5), 601–613. doi: 10.1007/s00262-006-0213-z.PubMedCrossRefGoogle Scholar
  169. 169.
    Holmes, J. P., Benavides, L. C., Gates, J. D., Carmichael, M. G., Hueman, M. T., Mittendorf, E. A., et al. (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(20), 3426–3433. doi: 10.1200/JCO.2007.15.7842.PubMedCrossRefGoogle Scholar
  170. 170.
    Gates, J. D., Clifton, G. T., Benavides, L. C., Sears, A. K., Carmichael, M. G., Hueman, M. T., et al. (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(47), 7476–7482. doi: 10.1016/j.vaccine.2010.09.029.PubMedCrossRefGoogle Scholar
  171. 171.
    Sears, A. K., Perez, S. A., Clifton, G. T., Benavides, L. C., Gates, J. D., Clive, K. S., et al. (2011). AE37: a novel T-cell-eliciting vaccine for breast cancer. Expert Opinion on Biological Therapy, 11(11), 1543–1550. doi: 10.1517/14712598.2011.616889.PubMedCrossRefGoogle Scholar
  172. 172.
    Hale, D., Perez, S., Sears, A., Clifton, G., Vreeland, T., Holmes, J., et al. (2011). P1-13-01: an update of a phase II trial of the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence. Cancer Research, 71(24 Supplement), P1-13-01-P11-13-01.CrossRefGoogle Scholar
  173. 173.
    Mittendorf, E. A., Schneble, E. J., Perez, S. A., Symanowski, R. P., Vreeland, T. J., Berry, J. S., et al. (2014). Primary analysis of the prospective, randomized, single-blinded phase II trial of AE37 vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients. Journal of Clinical Oncology, 32, 5s.CrossRefGoogle Scholar
  174. 174.
    Schneble, E. J., Berry, J. S., Trappey, A. F., Vreeland, T. J., Hale, D. F., Sears, A. K., et al. (2013). Vaccine-specific T-cell proliferation in response to a dual peptide cancer vaccine in breast and ovarian cancer patients. Journal for immunotherapy of cancer, 1(1), 1–1.CrossRefGoogle Scholar
  175. 175.
    Miyako, H., Kametani, Y., Katano, I., Ito, R., Tsuda, B., Furukawa, A., et al. (2011). Antitumor effect of new HER2 peptide vaccination based on B cell epitope. Anticancer Research, 31(10), 3361–3368.PubMedGoogle Scholar
  176. 176.
    Dakappagari, N. K., Douglas, D. B., Triozzi, P. L., Stevens, V. C., & Kaumaya, P. T. (2000). Prevention of mammary tumors with a chimeric HER-2 B-cell epitope peptide vaccine. Cancer Research, 60(14), 3782–3789.PubMedGoogle Scholar
  177. 177.
    Dakappagari, N. K., Pyles, J., Parihar, R., Carson, W. E., Young, D. C., & Kaumaya, P. T. (2003). A chimeric multi-human epidermal growth factor receptor-2 B cell epitope peptide vaccine mediates superior antitumor responses. Journal of Immunology, 170(8), 4242–4253.CrossRefGoogle Scholar
  178. 178.
    Kaumaya, P. T., Foy, K. C., Garrett, J., Rawale, S. V., Vicari, D., Thurmond, J. M., et al. (2009). Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors. Journal of Clinical Oncology, 27(31), 5270–5277. doi: 10.1200/JCO.2009.22.3883.PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Wiedermann, U., Wiltschke, C., Jasinska, J., Kundi, M., Zurbriggen, R., Garner-Spitzer, E., et al. (2010). A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a phase I study. Breast Cancer Research and Treatment, 119(3), 673–683.PubMedCrossRefGoogle Scholar
  180. 180.
    Schlom, J. (2012). Therapeutic cancer vaccines: current status and moving forward. Journal of the National Cancer Institute, 104(8), 599–613. doi: 10.1093/jnci/djs033.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Benavides, L. C., Gates, J. D., Carmichael, M. G., Patil, R., Holmes, J. P., Hueman, M. T., et al. (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(8), 2895–2904. doi: 10.1158/1078-0432.CCR-08-1126.PubMedCrossRefGoogle Scholar
  182. 182.
    Disis, M. L., Wallace, D. R., Gooley, T. A., Dang, Y., Slota, M., Lu, H., et al. (2009). Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. Journal of Clinical Oncology, 27(28), 4685–4692. doi: 10.1200/JCO.2008.20.6789.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Patil, R., Clifton, G. T., Litton, J. K., Shumway, N. M., Vreeland, T. J., Berry, J. S., et al. 2013 Safety and efficacy of the HER2-derived GP2 peptide vaccine in combination with trastuzumab for breast cancer patients in the adjuvant setting. In JOURNAL OF CLINICAL ONCOLOGY, (Vol. 31, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  184. 184.
    Cerullo, V., Diaconu, I., Kangasniemi, L., Rajecki, M., Escutenaire, S., Koski, A., et al. (2011). Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus. Molecular Therapy, 19(9), 1737–1746. doi: 10.1038/mt.2011.113.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Demaria, S., Volm, M. D., Shapiro, R. L., Yee, H. T., Oratz, R., Formenti, S. C., et al. (2001). Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clinical Cancer Research, 7(10), 3025–3030.PubMedGoogle Scholar
  186. 186.
    Emens, L. A., Asquith, J. M., Leatherman, J. M., Kobrin, B. J., Petrik, S., Laiko, M., 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. Journal of Clinical Oncology, 27(35), 5911–5918. doi: 10.1200/JCO.2009.23.3494.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Chen, G., Gupta, R., Petrik, S., Laiko, M., Leatherman, J. M., Asquith, J. M., et al. (2014). A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunology Research, 2(10), 949–961. doi: 10.1158/2326-6066.CIR-14-0058.PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Pruitt, S. K., Boczkowski, D., de Rosa, N., Haley, N. R., Morse, M. A., Tyler, D. S., et al. (2011). Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. European Journal of Immunology, 41(12), 3553–3563. doi: 10.1002/eji.201141383.PubMedCrossRefGoogle Scholar
  189. 189.
    Soliman, H. H., Minton, S. E., Ismail-Khan, R., Han, H. S., Vahanian, N. N., Link, C. J., et al. (2015). Abstract P2-15-04: A phase 1/2 study of Ad. p53 DC vaccine with indoximod immunotherapy in metastatic breast cancer. Cancer Res, 75(9 Supplement), P2-15-04-P12-15-04.Google Scholar
  190. 190.
    Hamid, O., Schmidt, H., Nissan, A., Ridolfi, L., Aamdal, S., Hansson, J., et al. (2011). A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. Journal of Translational Medicine, 9, 204. doi: 10.1186/1479-5876-9-204.PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P., & Wolchok, J. D. (2014). Immune modulation in cancer with antibodies. Annual Review of Medicine, 65, 185–202. doi: 10.1146/annurev-med-092012-112807.PubMedCrossRefGoogle Scholar
  192. 192.
    Saenger, Y., Magidson, J., Liaw, B., de Moll, E., Harcharik, S., Fu, Y., et al. (2014). Blood mRNA expression profiling predicts survival in patients treated with tremelimumab. Clinical Cancer Research, 20(12), 3310–3318. doi: 10.1158/1078-0432.CCR-13-2906.PubMedCrossRefGoogle Scholar
  193. 193.
    Shahabi, V., Berman, D., Chasalow, S. D., Wang, L., Tsuchihashi, Z., Hu, B., et al. (2013). Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. Journal of Translational Medicine, 11, 75. doi: 10.1186/1479-5876-11-75.PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., et al. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. The New England Journal of Medicine, 366(26), 2443–2454. doi: 10.1056/NEJMoa1200690.PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Grosso, J., Horak, C. E., Inzunza, D., Cardona, D. M., Simon, J. S., Gupta, A. K., et al. 2013 Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). In Journal of Clinical Oncology, (Vol. 31, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  196. 196.
    Callahan, M. K., Horak, C. E., Curran, M. A., Hollman, T., Schaer, D. A., Yuan, J., et al. 2013 Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab. In JOURNAL OF CLINICAL ONCOLOGY, (Vol. 31, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  197. 197.
    Wolchok, J. D., Kluger, H., Callahan, M. K., Postow, M. A., Rizvi, N. A., Lesokhin, A. M., et al. (2013). Nivolumab plus ipilimumab in advanced melanoma. The New England Journal of Medicine, 369(2), 122–133. doi: 10.1056/NEJMoa1302369.PubMedCrossRefGoogle Scholar
  198. 198.
    Postow, M. A., Cardona, D. M., Taube, J. M., Anders, R. A., Taylor, C. R., Wolchok, J. D., et al. (2014). Peripheral and tumor immune correlates in patients with advanced melanoma treated with nivolumab (anti-PD-1, BMS-936558, ONO-4538) monotherapy or in combination with ipilimumab. Journal of Translational Medicine, 12(Suppl 1), O8.PubMedCentralCrossRefGoogle Scholar
  199. 199.
    Ku, G. Y., Yuan, J., Page, D. B., Schroeder, S. E., Panageas, K. S., Carvajal, R. D., et al. (2010). Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting. Cancer, 116(7), 1767–1775.PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Postow, M. A., Yuan, J., Panageas, K., Bogatch, K., Callahan, M., Cheng, M., et al. 2012 Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3mg/kg). In JOURNAL OF CLINICAL ONCOLOGY, (Vol. 30, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  201. 201.
    Postow, M. A., Chasalow, S. D., Yuan, J., Kuk, D., Panageas, K. S., Cheng, M., et al. 2013 Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma. In JOURNAL OF CLINICAL ONCOLOGY, (Vol. 31, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  202. 202.
    Schindler, K., Harmankaya, K., Postow, M. A., Frantal, S., Bello, D., Ariyan, C. E., et al. 2013 Pretreatment levels of absolute and relative eosinophil count to improve overall survival (OS) in patients with metastatic melanoma under treatment with ipilimumab, an anti CTLA-4 antibody. In JOURNAL OF CLINICAL ONCOLOGY, (Vol. 31, Vol. 15): AMER SOC CLINICAL ONCOLOGY 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USAGoogle Scholar
  203. 203.
    Schindler, K., Harmankaya, K., Kuk, D., Mangana, J., Michielin, O., Hoeller, C., et al. Correlation of absolute and relative eosinophil counts with immune-related adverse events in melanoma patients treated with ipilimumab. In ASCO Annual Meeting Proceedings, 2014 (Vol. 32, pp. 9096, Vol. 15_suppl)Google Scholar
  204. 204.
    Adams, S., Gray, R. J., Demaria, S., Goldstein, L., Perez, E. A., Shulman, L. N., et al. (2014). Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. Journal of Clinical Oncology, 32(27), 2959–2966. doi: 10.1200/JCO.2013.55.0491.PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Loi, S., Sirtaine, N., Piette, F., Salgado, R., Viale, G., Van Eenoo, F., et al. (2013). Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. Journal of Clinical Oncology, 31(7), 860–867. doi: 10.1200/JCO.2011.41.0902.PubMedCrossRefGoogle Scholar
  206. 206.
    Mahmoud, S. M., Paish, E. C., Powe, D. G., Macmillan, R. D., Grainge, M. J., Lee, A. H., et al. (2011). Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. Journal of Clinical Oncology, 29(15), 1949–1955. doi: 10.1200/JCO.2010.30.5037.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Georgia Regents University Cancer CenterAugustaUSA
  2. 2.Tianjin Medical University Cancer Institute and HospitalTianjinChina

Personalised recommendations