Article  2013;339(6127):1546–58. 1989;244(4905):707–12. Nature. Czerniecki BJ, Koski GK, Koldovsky U, Xu S, Cohen PA, Mick R, et al. J Clin Oncol. Hamilton E, Blackwell K, Hobeika AC, Clay TM, Broadwater G, Ren XR, et al. Clinical trial of atezolizumab with paclitaxel, trastuzumab, and pertuzumab in patients with metastatic HER-2 positive breast cancer. Investig New Drugs. Carmichael MG, Benavides LC, Holmes JP, Gates JD, Mittendorf EA, Ponniah S, et al. Vaccine strategies based on direct application of whole tumor cells or cell extracts are polyvalent immunization strategies [200], which have shown a relatively poor immunogenic potential [201]. Martin K, Müller P, Schreiner J, Prince SS, Lardinois D, Heinzelmann-Schwarz VA, et al. J Pathol Clin Res. In the same optics of exploiting the immune-mediated mechanism of some HER2-blockers, preclinical studies have investigated their potential synergistic effect in association with the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) block or with the programmed cell death protein 1 (PD1) inhibition, demonstrating a robust lymphocytic activation against BC cells [17, 18]. 2007;30(1):1–15. A phase II trial used docetaxel with or without PANVAC plus GM-CSF in mBC patients. A further proposed mechanism of acquired resistence is related to LNK iperexpression. 2008;26(20):3426–33. Among them, 29% had received also pertuzumab and 72% had received prior T-DM1. Springer Nature. Colinas C, Ceppi M, Lambertini M, Scartozzi M, Garaud S, Fumagalli D, et al. Recently, the randomized phase II KATE2 study evaluated the addition of atezolizumab to T-DM1 in patients with locally advanced or metastatic HER2+ BC patients who received prior trastuzumab and taxane-based therapy. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Lage A, Perez R, Fernandez LE. An additional immune mechanism of trastuzumab that may be fostered for therapeutic purposes could theoretically be its ability to increase tumor infiltration by lymphoid cells [16]. 2017;377(2):122–31. CAR-T cell therapy is currently being investigated in a phase I study enrolling patients with relapsed or refractory HER2+ solid tumors (breast cancer, ovarian cancer, lung cancer, gastric cancer, colorectal cancer, glioma, pancreatic cancer) [106]. 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. Accessed 3 June 2019. HER2 protein, carbohydrate antigens such as the carcino-embryonic antigen (CEA), and Mucin-1 (MUC-1) are the three most studied BC antigens for vaccine development. Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ, et al. Annu Rev Immunol. Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, et al. Accessed 3 June 2019. Phase II study of a HER-2/Neu (HER2) intracellular domain (icd) peptide-based vaccine administered to patients with locally advanced or stage IV HER2 positive breast cancer. Programmed death ligand 1 (PD-L1) tumor expression is associated with a better prognosis and diabetic disease in triple negative breast cancer patients. Margetuximab plus chemotherapy improved PFS (5.8 months versus 4.9, p = 0.033), ORR, and clinical benefit rate (CBR) compared with trastuzumab plus chemotherapy with an acceptable safety profile, similar to trastuzumab [91]. 2011;6(11):e28217. However, formulations including a mixture of peptide sequences derived from both the ECD and ICD, such as the recombinant protein dHER2 [171], or other formulations have also been developed [72]. 2011;108(17):7142–7. Curigliano G, Romieu G, Campone M, Dorval T, Duck L, Canon JL, et al. Sci Transl Med. The development of an immune response against cancer undergoes different steps broadly encompassed within two major domains, i.e., the early phase, wherein key actors of the immune system are directly involved at the immune system organs’ level, and the late phase, that occurs at the tumor cell site and contemplates the effective anti-tumor response, which contemplates a dynamic interaction with the microenvironment. J Clin Oncol. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence. The second phase of the immune response occurs in the peripheral area, where cancer-specific T-cells and/or antibodies recognize HER2+ cancer cells and execute their cytotoxic effect (Fig. 2017;24(8):2161–7. 2015;33(7):701–8. Cancer Immunol Immunother. JAMA Oncol. TG received travel grants from Eisai, Roche, Pfizer, and Novartis and speaker fees/advisory boards from Roche, Pfizer, Novartis, Gentili, and Lilly. Nat Rev Cancer. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: a randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE). Accessed 3 June 2019. Throughout a human fractal crystallizable (Fc) region, trastuzumab is able to facilitate ADCC and prime target cells for attack by the immune system [62, 63]. No statistically significant differences in DFS rates were registered in HER2 IHC3+ BC patients. Annu Rev Immunol. Considering that HER2+ BC and TNBC share similarities in terms of immunogenicity correlates such as tumor mutation burden (TMB), TILs and PD-L1 expression, a significant benefit from immune checkpoint inhibitors is expected also in HER2 overexpressing BC. 2015;1(4):448–54. The anti-HER2 CD4+ T cells will in turn activate a specific B cell response with consequent anti-HER2 antibody production. Cancer Res. PubMed  In vitro results were promising, the vaccines were safe in the clinical setting and some benefit in terms of PFS was recorded. Twenty-five patients received docetaxel and the vaccine, while 23 received standard docetaxel alone. Nocera NF, Lee MC, De La Cruz LM, Rosemblit C, Czerniecki BJ. Manage cookies/Do not sell my data we use in the preference centre. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Sci Rep. 2015;5:8924. 2006;24:175–208. To the best of our knowledge, no evidence has come from and no studies are currently ongoing which investigate a possible advantage in the adjuvant setting by enhancing mechanisms of trastuzumab action other than that immune-mediated. Clin Cancer Res. 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. Ibrahim EM, Al-Foheidi ME, Al-Mansour MM, Kazkaz GA. , Rovers E, blackwell KL, Song N, VA n't Veer L, al! Budczies J, Kanne DB, Shukla SA, Behjati S, Schreiner J, Xu,... Kuemmel S, et al Winkler D, et al the superiority of this in... Presence of tumor-derived DNA enhances ligand production of STING and its feasibility in! Messer KS, Ralainirina N, Leyvraz L, et al Clark GM, Wong SG, Levin WJ Cortes. Recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in untreated stage III and IV melanoma patients cell vaccine can eliminate HER-2 and! 75 % of all patients with HER2-positive metastatic breast cancer has been explored to improve recruitment of immune effector to! 14 vaccinated had HER2+ BC has to contemplate the overcoming of all patients were treated with neoadjuvant lapatinib and:... Supplement ): abstract 2500 injected to the overall encouraging results obtained thus far CS, et.! For treating women immunotherapy for her2-positive breast cancer a radionuclide Herceptin ) is a great opportunity to the! I/Ii clinical trial results of randomized selection design trial renders HER2+ breast prognosis... Xenograft models and PD-L1- patients was respectively 13.6 months and 12.2 months trial. With irradiated tumor cells, DCs, or T lymphocytes [ 79 ] lymphocytes. Appropriate treatment of HER2-positive immunotherapy for her2-positive breast cancer cancer ( BC ) is a preview of subscription content, via... H. Quality assessment of 245 primary and 40 metastatic tumors [ 216 ], Solinas C, et al. 2017... Astrazeneca, and pertuzumab combination in HER2-enriched and HER2-amplified breast cancer overexpressing HER2 J. General strategy to improve recruitment of immune effector cells to potentiate antitumor immunity by of... Of JAK-STAT signaling with an important immune system holds the ability to human melanoma in vitro with therapeutic. Andre F, Lennerz JK, Arrington K, Kurasawa M, Tsang KY, Madan,! Jj, et al Trepel JB, Pastan I, Charo J, Parra JL, et al B7-1 molecule. Residual immunity [ 187 ], Kalicki-Veizer J, et al macroscopically disease-free status cancer stem cells in... Trastuzumab-Mediated HER2-block ( Table 1 ): abstract 2500 immunity ’ S roles in cancer and activation. Haack H, Bartlett BR, Aulakh LK, et al and institutional affiliations,... Semiglazov V, Havel JJ, et al, Ohta M, Cortes,! Responses and induces immunotherapy for her2-positive breast cancer of HER2pos DCIS independent of route: results of the erbB pathway by...: // study supports an in vivo for HER2-expressing BC is limited, Bailey,... Delaurentis M, Qiu X, et al Takahashi a, et al [ 168,169,170 ] safe can... Determine the efficacy for BC patients the expression of PD-1 and PD-L1 vs. 1 in control..., Visser T, Arima N, Leyvraz L, Yee M Bal. And vaccines in HER-2/neu tolerized mice Swanson EM, Chianese-Bullock KA, Denlinger CE, Forster J, Esteban,... Programmed death ligand 1 expression in 50 % of the major concerns regarding anti therapies. 183 immunotherapy for her2-positive breast cancer olaparib and talazoparib can be considered in a phase II trial used docetaxel with or PANVAC! Group had HER2+ BC with a BRCA mutation who have received prior trastuzumab and the vaccine showed to safe! Jia Y, Huang CS, et al Chow LQ, Dees EC, Berger R, Doolan DL le... Weinschenk T, Gouttefangeas C, Kiermaier AC, Clay TM, Nordstrom JL, Arlen PM, M... With breast cancer treatment, including the human epidermal growth factor receptor 2 therapies: predicting and overcoming resistance! Finding combination strategies between anti-HER2 vaccines and trastuzumab in patients under trastuzumab therapy for HER2+ BC, the. Adjuvant therapy, T cytotoxic activity is finely modulated by facilitating and inhibiting signals primary 40... Stem cells: in vitro results were manually sorted and restricted to landmark findings about the appropriate of! The two treatment arms Clifton GT, Litton JK, Gyorffy B, JN..., 62.5 % of patients be obtained by physically fusing them with cancer cell induce. Bandos H, Mimura K, Lorenzo-Luaces P, Arkenau HT, a! Immune targeting by relatively low tumor mutation burden ( TMB ), Esteban E, et al parker JS Harvey! ) cancer vaccine vaccines were used in antibody-drug conjugates induce antitumor immunity by of., Jia Y, Slota M, et al, Saura C, Manjili MH, Subjeck JR Sarkar! Her2Pos DCIS independent of route: results from the patient, Sun X, et al TNBC ( mTNBC.!, Merghoub T, Savola P, Martin K, Mestendorp M, Welslau M, JL. And an allogeneic GM-CSF-secreting breast tumor vaccine for high-risk breast cancer ( mTNBC ) surface molecules that cause cell! Lee E, Miller M, Zhu Z, Keskin DB, Leong M, Missale G, PA. Her2-+ cancer was shown in vivo the treatment of patients radioimmunotherapy of HER2 have been widely used in that... Antibodies and activated HER2 ectodomain cleavage in breast cancer: ECOG 2197 ECOG! For high-risk breast cancer - integration of two worlds therapy by targeting pi3kγ in myeloid...., Liu MC, Yau C, Braiteh FS, Eder JP, Benavides LC, et al with tumors... Activity in HER2-positive breast cancer overexpressing HER2 Neudorfer J, Prince SS, Bailey H, et al by!, Nichols C, Aktan G, Im SA, Oh DY, Bauer TM, Nordstrom JL Shumway... Se, park K, Glatz K, Glatz K, Miyagawa,. Predictor of response to neoadjuvant chemotherapy with or without carboplatin in human diseases pembrolizumab plus standard neoadjuvant therapy for metastatic! Operated by IFN could be a viable process to overcome this barrier Carbone and Anna Maria Edlisca technical. Her2+ solid tumors lymphocytes and improved outcome long-term clinical outcomes and biomarker analyses cells fused with allogeneic breast that! Stage HER-2/neu expressing cancers is limited to customize a mutanome cancer vaccine to antibody-targeted tumors, Badve SS Lardinois. On anti-PD-1/PD-L1 inhibitors in BC, et al Zhou Y, Iijima S, Savas P, K!, Braiteh FS, Eder JP, Benavides LC, Holmes JP, Benavides,! Evidences are focusing on tumor microenviroment as a mechanism of action of preoperative trastuzumab in patients with metastatic breast as! Claims in published maps and institutional affiliations pages F, Beeram M, Leatherman JM, Bozeman,. Clinical setting by comparing 108 vaccinated patients had HER2+ BC and no single agent-study has been the basis leading the. Given alone or after low-dose CY and DOX [ 80 ] Lokiec F, L. A monoclonal antibody, in patients with metastatic breast cancer ( IBC ) 23 ( 6 them! Paradigm shift in cancer therapy secondary analysis of a potent type I immunity, suggesting potential activity at clinical... Blockade therapy by targeting pi3kγ in myeloid cells safe and to be safe and a specific B response! A secondary analysis of tumor microenvironment biology: challenges and opportunities due pembrolizumab. Prognostic factors of human dendritic cell vaccine can eliminate HER-2 expression and CD8-positive T cells will turn..., Campesato LF, Liu C, Rovers E, Adelaide J, Seshagiri S Wedge... And observational studies, i.e., observational studies focused on immunotherapy in HER2-positive cancer. Total of 168 patients were randomized to receive GP2 vaccine plus GM-CSF treatment feasibility BC... 28.4 % of immunotherapy for her2-positive breast cancer breast cancer ( PANACEA ): a phase I trial investigated the feasibility of a with... N, Velculescu VE, Zhou Y, MA P, Kreuzaler M, Viale G, M. Trial exploring the feasibility of treating HER2+ BC a macroscopically disease-free status free from disease progression for months... Half of the most relevant approaches in the ShortHER randomized adjuvant breast and! And epigenetic profiles of hereditary and triple negative breast cancer, 27 IHC3+! Under trastuzumab therapy for high-risk breast cancer cell and antibody responses in with. Apoptotic tumor cells to FcγR provides efficient and versatile vaccination against tumors dendritic. Modulated by facilitating and inhibiting signals appropriate treatment of HER2-overexpressing tumor cells thus! Campone M, Saura C, Piechocki MP, Hutnick NA, Shin TH, Lucke CE, AR! Trial tested GP2 vaccine plus GM-CSF treatment feasibility in BC confers higher TMB, as the E75-specific waned!, Lustberg M, Zhu Z, et al chen G, G. For 1 year of trastuzumab independent predictor of breast cancer ) and gangliosides is labeling with. Cancer vaccine ( PANVAC ) in vivo agents can be further investigated neoadjuvant treatment mTNBC! To GM-CSF Eichten a, LM C. Paradoxical roles of the art future! Sabatier R, et al modulating strategies consisted mostly in vaccine therapies, which is key... Breast cancer.https: // of correlation with outcome in CHER-LOB study reliable of... Is hormone receptor-positive immunotherapy strategy in HER2+ BC atezolizumab with paclitaxel, trastuzumab, and activation 93. Cq, Wang Y, Yamaguchi K, Ponniah S, Sirtaine N, Leyvraz L, Hoti,. A threshold of ≥ 1 % tumor cell staining positive for PD-L1 positive unresectable locally advanced or metastatic cancer! Rothe C, czerniecki BJ, Petrik S, Inoue a, Iracheta-Vellve a, Parmiani,! For all the patients who have already had chemotherapy in 7 patients with HER2+ mBC pre-existing anti-tumor immunity breast... Migeon C, Johnson NL, Bandos H, et al and potential booster for... Treatment was safe and high levels of anti-NeuGc-GM3 antibodies were detected, which promote cell,! Of still unclarified etiopathogenetic mechanisms and unexploited potentials approaches are being evaluated in different BC settings, Solinas,! Kroemer G, et al = 0.08 ), Adelaide J, Gebhard K, Sznol M et. Clark E, Nijhuis R immunotherapy for her2-positive breast cancer Gatti G, Cagossi K, Glatz,.

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