Breast Cancer Immunotherapy: An Update

Issam Makhoul, Mohammad Atiq, Ahmed Alwbari, Thomas Kieber-Emmons, Issam Makhoul, Mohammad Atiq, Ahmed Alwbari, Thomas Kieber-Emmons

Abstract

The immune system plays a major role in cancer surveillance. Harnessing its power to treat many cancers is now a reality that has led to cures in hopeless situations where no other solutions were available from traditional anticancer drugs. These spectacular achievements rekindled the oncology community's interest in extending the benefits to all cancers including breast cancer. The first section of this article reviews the biological foundations of the immune response to different subtypes of breast cancer and the ways cancer may overcome the immune attack leading to cancer disease. The second section is dedicated to the actual immune treatments including breast cancer vaccines, checkpoint inhibitors, monoclonal antibodies, and the "unconventional" immune role of chemotherapy.

Keywords: Breast cancer; immune dormancy; immunotherapy.

Conflict of interest statement

Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Antigen-presenting cells (APCs) process tumor-associated antigens (TAAs) and present them in combination with MHC surface proteins to T-cell receptor (TCR) on T-helper cells (MHC-II) and some CD8+ T cells (MHC-I). In the beginning of the immune reaction, costimulatory signals (CD27, CD28, CD40, OX40, 4-1BB, GITR, and ICOS surface proteins on T cells) help intensify the activation of naïve helper or cytotoxic T cells. As the immune reaction reaches its goal of eliminating the transformed cells, inhibitory signals (CTLA-4, PD-1, and LAG-3) help wind down T-cell activation. The expression of the inhibitory molecules by the transformed cells or other cells in the tumor microenvironment leads to local immunosuppression and the persistence of cancer cells. Inhibitory monoclonal antibodies (MAbs) targeting CTLA-4, PD-1, or PD-L1 have opened the way to a new era in IO. Targeting stimulatory pathways with agonist MAbs is being explored by multiple clinical trials (see below). Bispecific antibodies (BsABs) target T-cell surface receptors such as CD3 and TAA and recruit other effector cells through the Fc receptor such as macrophages or natural killer cells.
Figure 2.
Figure 2.
Immune and angiogenic dormancy in maintaining the cancer at a microscopic size. (A) Once the tumor undergoes immune escape and the angiogenic switch is turned on, the tumor grows locally and spreads metastases. In this model, DTCs are released at a later stage because DTCs do not gain access to the bloodstream until the tumor has acquired its own vasculature. (B) Another model stipulates that dissemination of cancer cells may occur very early in the beginning of the nascent cancer and continues throughout its growth and development. In this model, the role of immune escape is more important than the role of the angiogenic switch because microscopic tumors (and even in situ tumors) may spawn DTCs/micrometastasis before the angiogenic switch has taken place. DTCs indicate disseminated tumor cells.

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. doi:10.3322/caac.21442.
    1. Loi S, Sirtaine N, Piette F, et al. 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. J Clin Oncol. 2013;31:860–867. doi:10.1200/JCO.2011.41.0902.
    1. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25:1544–1550. doi:10.1093/annonc/mdu112.
    1. Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD, Nielsen TO. CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012;14:R48.
    1. Adams S, Gray RJ, Demaria S, et al. 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. J Clin Oncol. 2014;32:2959–2966. doi:10.1200/jco.2013.55.0491.
    1. Dieci MV, Criscitiello C, Goubar A, et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol. 2014;25:611–618. doi:10.1093/annonc/mdt556.
    1. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105–113. doi:10.1200/JCO.2009.23.7370.
    1. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983–991. doi:10.1200/JCO.2014.58.1967.
    1. Kieber-Emmons T, Kohler H. Evolutionary origin of autoreactive determinants (autogens). Proc Natl Acad Sci U S A. 1986;83:2521–2525.
    1. Milstein O, Hagin D, Lask A, et al. CTLs respond with activation and granule secretion when serving as targets for T-cell recognition. Blood. 2011;117:1042–1052. doi:10.1182/blood-2010.
    1. Andersen MH, Schrama D, thor Straten P, Becker JC. Cytotoxic T cells. J Invest Dermatol. 2006;126:32–41.
    1. Tai X, Cowan M, Feigenbaum L, Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005;6:152–162.
    1. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases—elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25.
    1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570.
    1. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–998.
    1. Croxford JL, Tang ML, Pan MF, et al. ATM-dependent spontaneous regression of early Eµ-myc-induced murine B-cell leukemia depends on natural killer and T cells. Blood. 2013;121:2512–2521. doi:10.1182/blood-2012.
    1. Senovilla L, Vitale I, Martins I, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science. 2012;337:1678–1684. doi:10.1126/science.1224922.
    1. Wu X, Peng M, Huang B, et al. Immune microenvironment profiles of tumor immune equilibrium and immune escape states of mouse sarcoma. Cancer Lett. 2013;340:124–133.
    1. Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–271. doi:10.1093/annonc/mdu450.
    1. Dieci MV, Griguolo G, Miglietta F, Guarneri V. The immune system and hormone-receptor positive breast cancer: is it really a dead end? Cancer Treat Rev. 2016;46:9–19.
    1. Baumgarten SC, Frasor J. Minireview: inflammation: an instigator of more aggressive estrogen receptor (ER) positive breast cancers. Mol Endocrinol. 2012;26:360–371.
    1. Jinushi M, Komohara Y. Tumor-associated macrophages as an emerging target against tumors: creating a new path from bench to bedside. Biochim Biophys Acta. 2015;1855:123–130.
    1. Lee HJ, Song IH, Park IA, et al. Differential expression of major histocompatibility complex class I in subtypes of breast cancer is associated with estrogen receptor and interferon signaling. Oncotarget. 2016;7:30119–30132. doi:10.18632/oncotarget.8798.
    1. Pierdominici M, Maselli A, Colasanti T, et al. Estrogen receptor profiles in human peripheral blood lymphocytes. Immunol Lett. 2010;132:79–85.
    1. Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. 2004;3:97–104.
    1. Inoue M, Mimura K, Izawa S, et al. Expression of MHC class I on breast cancer cells correlates inversely with HER2 expression. Oncoimmunology. 2012;1:1104–1110.
    1. Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer. 2009;9:274.
    1. Montecino-Rodriguez E, Berent-Maoz B, Dorshkind K. Causes, consequences, and reversal of immune system aging. J Clin Invest. 2013;123:958–965.
    1. Bonafe M, Storci G, Franceschi C. Inflamm-aging of the stem cell niche: breast cancer as a paradigmatic example. Bioessays. 2012;34:40–49.
    1. Irahara N, Miyoshi Y, Taguchi T, Tamaki Y, Noguchi S. Quantitative analysis of aromatase mRNA expression derived from various promoters (I. 4, I. 3, PII and I. 7) and its association with expression of TNF-α, IL-6 and COX-2 mRNAs in human breast cancer. Int J Cancer. 2006;118:1915–1921.
    1. Prieto GA, Rosenstein Y. Oestradiol potentiates the suppressive function of human CD4 CD25 regulatory T cells by promoting their proliferation. Immunology. 2006;118:58–65.
    1. Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. 2006;84:370–378.
    1. Nadkarni S, McArthur S. Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol. 2013;13:576–581.
    1. Svoronos N, Perales-Puchalt A, Allegrezza MJ, et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 2017;7:72–85. doi:10.1158/-16-0502.
    1. Rossini A, Rumio C, Sfondrini L, et al. Influence of antibiotic treatment on breast carcinoma development in proto-neu transgenic mice. Cancer Res. 2006;66:6219–6224. doi:10.1158/0008-5472.CAN-05-4592.
    1. Kassayova M, Bobrov N, Strojny L, et al. Preventive effects of probiotic bacteria Lactobacillus plantarum and dietary fiber in chemically-induced mammary carcinogenesis. Anticancer Res. 2014;34:4969–4975.
    1. Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH. Antibiotic use in relation to the risk of breast cancer. JAMA. 2004;291:827–835.
    1. Rutkowski MR, Stephen TL, Svoronos N, et al. Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell. 2015;27:27–40.
    1. Folkman J, Watson K, Ingber D, Hanahan D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature. 1989;339:58–61. doi:10.1038/339058a0.
    1. Rhim AD, Thege FI, Santana SM, et al. Detection of circulating pancreas epithelial cells in patients with pancreatic cystic lesions. Gastroenterology. 2014;146:647–651. doi:10.1053/j.gastro.2013.12.007.
    1. Gruber IV, Hartkopf AD, Hahn M, et al. Relationship between hematogenous tumor cell dissemination and cellular immunity in DCIS patients. Anticancer Res. 2016;36:2345–2351.
    1. Sänger N, Effenberger KE, Riethdorf S, et al. Disseminated tumor cells in the bone marrow of patients with ductal carcinoma in situ. Int J Cancer. 2011;129:2522–2526.
    1. Hill RP, Perris R. “Destemming” cancer stem cells. J Natl Cancer Inst. 2007;99:1435–1440.
    1. Chaffer CL, Weinberg RA. How does multistep tumorigenesis really proceed? Cancer Discov. 2015;5:22–24. doi:10.1158/.
    1. Kreso A, Dick JE. Evolution of the cancer stem cell model. Cell Stem Cell. 2014;14:275–291.
    1. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–728.
    1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-3988. doi:10.1073/pnas.0530291100.
    1. Al-Hajj M. Cancer stem cells and oncology therapeutics. Curr Opin Oncol. 2007;19:61–64. doi:10.1097/CCO.0b013e328011a8d6.
    1. Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16:225–238.
    1. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature. 2008;456:593–598.
    1. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers. 2014;6:1670–1690.
    1. Raggi C, Mousa H, Correnti M, Sica A, Invernizzi P. Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies. Oncogene. 2016;35:671–682.
    1. Scheel C, Eaton EN, Li SH, et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011;145:926–940.
    1. Mao Y, Qu Q, Chen X, Huang O, Wu J, Shen K. The prognostic value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis. PLoS ONE. 2016;11:e0152500.
    1. Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–1955. doi:10.1200/JCO.2010.30.5037.
    1. Robbins PF, Lu Y, El-Gamil M, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013;19:747–752.
    1. van Rooij N, van Buuren MM, Philips D, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31:e439–e442. doi:10.1200/JCO.2012.47.7521.
    1. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–1558. doi:10.1126/science.1235122.
    1. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.
    1. Luen S, Virassamy B, Savas P, Salgado R, Loi S. The genomic landscape of breast cancer and its interaction with host immunity. Breast. 2016;29:241–250.
    1. Nik-Zainal S, Alexandrov LB, Wedge DC, et al. Mutational processes molding the genomes of 21 breast cancers. Cell. 2012;149:979–993.
    1. Haricharan S, Bainbridge MN, Scheet P, Brown PH. Somatic mutation load of estrogen receptor-positive breast tumors predicts overall survival: an analysis of genome sequence data. Breast Cancer Res Treat. 2014;146:211–220.
    1. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–2199.
    1. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–128. doi:10.1126/science.aaa1348.
    1. Brown SD, Warren RL, Gibb EA, et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24:743–750. doi:10.1101/gr.165985.113.
    1. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res. 2011;13:R126.
    1. Perez EA, Thompson EA, Ballman KV, et al. Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the north central cancer treatment group n9831 adjuvant trastuzumab trial. J Clin Oncol. 2015;33:701–708. doi:10.1200/JCO.2014.57.6298.
    1. Ladoire S, Mignot G, Dabakuyo S, et al. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pathol. 2011;224:389–400.
    1. Criscitiello C. Tumor-associated antigens in breast cancer. Breast Care (Basel). 2012;7:262–266. doi:10.1159/000342164.
    1. Downs-Holmes C, Silverman P. Breast cancer: overview & updates. Nurse Pract. 2011;36:20–26; quiz 7. doi:10.1097/01.NPR.0000407602.29522.d7.
    1. Mittendorf EA, Clifton GT, Holmes JP, et al. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann Oncol. 2014;25:1735–1742. doi:10.1093/annonc/mdu211.
    1. Schneble EJ, Berry JS, Trappey FA, et al. The HER2 peptide nelipepimut-S (E75) vaccine (NeuVax™) in breast cancer patients at risk for recurrence: correlation of immunologic data with clinical response. Immunotherapy. 2014;6:519–531.
    1. Mittendorf EA. Efficacy and safety study of NeuVax™ (nelipepimut-S or E75) vaccine to prevent breast cancer recurrence (PRESENT). . Updated 2015. Accessed January 2, 2017.
    1. Clifton G, Holmes J, Perez S, et al. 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 Res. 2009;69:5110.
    1. Schneble EJ, Perez SA, Murray JL, et al. Primary analysis of the prospective, randomized, phase II trial of GP2+GM-CSF vaccine versus GM-CSF alone administered in the adjuvant setting to high-risk breast cancer patients. J Clin Oncol. 2014;32:134.
    1. Sears AK, Perez SA, Clifton GT, et al. AE37: a novel T-cell-eliciting vaccine for breast cancer. Expert Opin Biol Ther. 2011;11:1543–1550.
    1. Mittendorf EA, Ardavanis A, Symanowski J, et al. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence. Ann Oncol. 2016;27:1241–1248. doi:10.1093/annonc/mdw150.
    1. Lowenfeld L, Mick R, Datta J, et al. Dendritic cell vaccination enhances immune responses and induces regression of HER2(pos) DCIS independent of route: results of randomized selection design trial. Clin Cancer Res. 2017;23:2961–2971. doi:10.1158/1078-0432.CCR.
    1. Finn OJ. The dawn of vaccines for cancer prevention. Nat Rev Immunol. 2018;18:183–194.
    1. Blixt O, Bueti D, Burford B, et al. Autoantibodies to aberrantly glycosylated MUC1 in early stage breast cancer are associated with a better prognosis. Breast Cancer Res. 2011;13:R25.
    1. Ibrahim NK, Murray JL, Zhou D, et al. Survival advantage in patients with metastatic breast cancer receiving endocrine therapy plus sialyl tn-KLH vaccine: post hoc analysis of a large randomized trial. J Cancer. 2013;4:577–584.
    1. Sandrin MS, Vaughan HA, Xing P, McKenzie IF. Natural human anti-Gal alpha(1,3)Gal antibodies react with human mucin peptides. Glycoconj J. 1997;14:97–105.
    1. Butschak G, Karsten U. Isolation and characterization of Thomsen-Friedenreich-specific antibodies from human serum. Tumour Biol. 2002;23:113–122.
    1. Andre F, Dieci MV, Dubsky P, et al. Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin Cancer Res. 2013;19:28–33. doi:10.1158/1078-0432.CCR.
    1. Kurtenkov O, Klaamas K, Mensdorff-Pouilly S, Miljukhina L, Shljapnikova L, Chužmarov V. Humoral immune response to MUC1 and to the Thomsen-Friedenreich (TF) glycotope in patients with gastric cancer: relation to survival. Acta Oncol. 2007;46:316–323.
    1. Monzavi-Karbassi B, Pashov A, Kieber-Emmons T. Tumor-associated glycans and immune surveillance. Vaccines. 2013;1:174–203.
    1. Kieber-Emmons T, Saha S, Pashov A, Monzavi-Karbassi B, Murali R. Carbohydrate-mimetic peptides for pan anti-tumor responses. Front Immunol. 2015;5:308.
    1. Makhoul I, Hutchins L, Emanuel PD, et al. Moving a carbohydrate mimetic peptide into the clinic: clinical response of a breast cancer patient after mimotope-based immunotherapy. Hum Vaccin Immunother. 2015;11:37–44.
    1. Hennings L, Artaud C, Jousheghany F, Monzavi-Karbassi B, Pashov A, Kieber-Emmons T. Carbohydrate mimetic peptides augment carbohydrate-reactive immune responses in the absence of immune pathology. Cancers. 2011;3:4151–4169.
    1. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin adjuvant (HERA) trial. Lancet. 2017;389:1195–1205.
    1. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32:3744–3752. doi:10.1200/JCO.2014.55.5730.
    1. Slamon DJ, Eiermann W, Robert NJ, et al. Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab in HER2-positive early breast cancer. Paper presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX.
    1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792.
    1. Joensuu H, Kellokumpu-Lehtinen P, Bono P, et al. Trastuzumab in combination with docetaxel or vinorelbine as adjuvant treatment of breast cancer: the FinHer trial. Breast Cancer Res Treat. 2005;94:S5.
    1. Spielmann M, Roché H, Delozier T, et al. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009;27:6129–6134.
    1. Ingold Heppner B, Untch M, Denkert C, et al. Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer. Clin Cancer Res. 2016;22:5747–5754. doi:10.1158/1078-0432.CCR-15-2338.
    1. Carbognin L, Pilotto S, Nortilli R, et al. Predictive and prognostic role of tumor-infiltrating lymphocytes for early breast cancer according to disease subtypes: sensitivity analysis of randomized trials in adjuvant and neoadjuvant setting. Oncologist. 2016;21:283–291. doi:10.1634/theoncologist.2015-0307.
    1. Bense RD, Sotiriou C, Piccart-Gebhart MJ, et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J Natl Cancer Inst. 2016;109:djw192. doi:10.1093/jnci/djw192.
    1. Piccart-Gebhart M, Holmes E, Baselga J, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol. 2016;34:1034–1042. doi:10.1200/JCO.2015.62.1797.
    1. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1688–1700.
    1. Thomas A, Teicher BA, Hassan R. Antibody-drug conjugates for cancer therapy. Lancet Oncol. 2016;17:e254–e262.
    1. Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther. 2017;181:126–142.
    1. Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18:732–742.
    1. Yao S, Zhu Y, Chen L. Advances in targeting cell surface signalling molecules for immune modulation. Nat Rev Drug Discov. 2013;12:130–146.
    1. Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol. 2016;47:78–84.
    1. Muenst S, Schaerli A, Gao F, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146:15–24.
    1. Nanda R, Chow LQ, Dees EC, et al. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib keynote-012 study. J Clin Oncol. 2016;34:2460–2467.
    1. Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. J Clin Oncol. 2017;35(15_suppl):1008.
    1. Adams S, Loi S, Toppmeyer D, et al. Phase 2 study of pembrolizumab as first-line therapy for PD-L1-positive metastatic triple-negative breast cancer (mTNBC): preliminary data from KEYNOTE-086 cohort B. J Clin Oncol. 2017; 35(15_suppl):1088
    1. Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. Cancer Res. 2017; 77(13_supp):2986 DOI: 10.1158/1538-7445.AM2017-2986
    1. Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017;35(15_Supp):506.
    1. Cortes Castan J, Guo Z, Karantza V, Aktan G. 234TiPKEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab (pembro) chemotherapy (chemo) vs placebo (PBO) chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2017;(28) (5 Supplement), 1 September 2017, mdx364.016,
    1. Adams S, Diamond JR, Hamilton EP, et al. Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016;34(15_Supp):1009.
    1. Emens LA, Adams S, Loi S, et al. IMpassion130: a phase III randomized trial of atezolizumab with nab-paclitaxel for first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2016.
    1. Gatalica Z, Snyder C, Maney T, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev. 2014;23:2965–2970. doi:10.1158/1055-9965.EPI.
    1. Pusztai L. Pembrolizumab in treating patients with triple-negative breast cancer. . Updated 2016. Accessed January 2, 2017.
    1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–723.
    1. Urba WJ. Safety study of enoblituzumab (MGA271) in combination with ipilimumab in refractory cancer. . Updated 2016. Accessed December 25, 2016.
    1. Connolly R. Entinostat, nivolumab, and ipilimumab in treating patients with solid tumors that are metastatic or cannot be removed by surgery or locally advanced or metastatic HER2-negative breast cancer. . Updated 2016. Accessed December 25, 2016.
    1. Santa-Maria C. MEDI4736 and tremelimumab in treating patients with metastatic HER2 negative breast cancer. . Updated 2016. Accessed December 25, 2016.
    1. Vonderheide RH, LoRusso PM, Khalil M, et al. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res. 2010;16:3485–3494. doi:10.1158/1078-0432.CCR.
    1. Page DB, Diab A, Yuan J, et al. Pre-operative immunotherapy with tumor cryoablation (cryo) plus ipilimumab (ipi) induces potentially favorable systemic and intratumoral immune effects in early stage breast cancer (ESBC) patients. J Immunother Cancer. 2015;3:O6.
    1. Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology. 2015;29:375–375.
    1. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–6587. doi:10.1158/1078-0432.CCR.
    1. Naidoo J, Wang X, Woo K, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35:709–717.
    1. Brignone C, Gutierrez M, Mefti F, et al. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J Transl Med. 2010;8:71.
    1. Cabo M, Offringa R, Zitvogel L, Kroemer G, Muntasell A, Galluzzi L. Trial watch: immunostimulatory monoclonal antibodies for oncological indications. Oncoimmunology. 2017;6:e1371896.
    1. Naghavi AO, Johnstone PA, Kim S. Clinical trials exploring the benefit of immunotherapy and radiation in cancer treatment: a review of the past and a look into the future. Curr Probl Cancer. 2016;40:38–67.
    1. Cheuk AT, Mufti GJ, Guinn B. Role of 4-1BB:4-1BB ligand in cancer immunotherapy. Cancer Gene Ther. 2004;11:215–226.
    1. Kohrt HE, Houot R, Weiskopf K, et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest. 2012;122:1066–1075. doi:10.1172/JCI61226.
    1. Moran AE, Kovacsovics-Bankowski M, Weinberg AD. The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy. Curr Opin Immunol. 2013;25:230–237.
    1. Slobodova Z, Ehrmann J, Krejci V, Zapletalova J, Melichar B. Analysis of CD40 expression in breast cancer and its relation to clinicopathological characteristics. Neoplasma. 2011;58:189–197.
    1. Kim H, Kim Y, Bae S, et al. Direct interaction of CD40 on tumor cells with CD40L on T cells increases the proliferation of tumor cells by enhancing TGF-β production and Th17 differentiation. PLoS ONE. 2015;10:e0125742.
    1. Wang Z, Wang J, Ling W, Zhang X, Shi Q. Effects of CD40 ligation combined with chemotherapy drugs on human breast cancer cell lines. J Int Med Res. 2013;41:1495–1504.
    1. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21:15–25.
    1. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39:74–88.
    1. Sevko A, Michels T, Vrohlings M, et al. Antitumor effect of paclitaxel is mediated by inhibition of myeloid-derived suppressor cells and chronic inflammation in the spontaneous melanoma model. J Immunol. 2013;190:2464–2471. doi:10.4049/jimmunol.1202781.
    1. Ge Y, Domschke C, Stoiber N, et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother. 2012;61:353–362.
    1. Schiavoni G, Sistigu A, Valentini M, et al. Cyclophosphamide synergizes with type I interferons through systemic dendritic cell reactivation and induction of immunogenic tumor apoptosis. Cancer Res. 2011;71:768–778. doi:10.1158/0008-5472.CAN.
    1. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28:690–714.
    1. Alizadeh D, Trad M, Hanke NT, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 2014;74:104–118. doi:10.1158/0008-5472.CAN.
    1. Tsavaris N, Kosmas C, Vadiaka M, Kanelopoulos P, Boulamatsis D. Immune changes in patients with advanced breast cancer undergoing chemotherapy with taxanes. Br J Cancer. 2002;87:21–27.
    1. Demaria S, Volm MD, Shapiro RL, et al. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 2001;7:3025–3030.
    1. Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. 2011;33:369–383.
    1. Liu W, Fowler D, Smith P, Dalgleish A. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer. 2010;102:115–123.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj