Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study

M Higgins, G Curigliano, V Dieras, S Kuemmel, G Kunz, P A Fasching, M Campone, T Bachelot, P Krivorotko, S Chan, A Ferro, L Schwartzberg, M Gillet, P M De Sousa Alves, V Wascotte, F F Lehmann, P Goss, M Higgins, G Curigliano, V Dieras, S Kuemmel, G Kunz, P A Fasching, M Campone, T Bachelot, P Krivorotko, S Chan, A Ferro, L Schwartzberg, M Gillet, P M De Sousa Alves, V Wascotte, F F Lehmann, P Goss

Abstract

Purpose: This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms' tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients.

Methods: Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab-chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A-C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination.

Results: Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely.

Conclusions: Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab-chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves.

Keywords: Breast cancer; Immunogenicity; Immunotherapy; Neoadjuvant therapy; Safety; WT1 antigen.

Conflict of interest statement

Conflict of interest

MH, SC, LS, GC, GK, MC, AF, PK, SK, and PG have no conflict of interest. TB reports grant, personal fees, and non-financial support from Roche and Novartis outside the submitted work. VD reports personal fees from Lilly for her participation to advisory boards, from Roche Genentech, Novartis, and Pfizer for her participation to advisory boards and symposium, and from GSK for her participation to symposium, outside the submitted work. PAF reports grant from Amgen and Novartis, and personal fees from Amgen, Novartis, Celgene, Pfizer, GSK, and Genomic Health, outside the submitted work. PMDSA and FFL were employees of the GSK group of companies during the conduct of the study. VW and MG are employees of the GSK group of companies. VW and FFL hold shares in the GSK group of companies as part of her/his employee remuneration.

Ethical standards

All procedures performed in this study were in accordance with the ethical standards of the national independent ethics committees and institutional review boards of the study centers. The study was conducted in accordance with Good Clinical Practice and all applicable regulatory requirements, including the Declaration of Helsinki.

Figures

Fig. 1
Fig. 1
Participant flow N, number of patients; WT1 patients who received WT1-immunotherapeutic; ATP cohort, according-to-protocol cohort for immunogenicity; SAE serious adverse event; pIMD potential immune-mediated disease; PD progressive disease; Cohort A: post-menopausal patients with hormone receptor-positive breast cancer receiving AIs as neoadjuvant therapy; Cohort B: patients receiving neoadjuvant chemotherapy; Cohort C: patients with human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer receiving neoadjuvant trastuzumab therapy combined with chemotherapy; Cohort D: patients with hormone receptor-positive/HER2-negative breast cancer receiving neoadjuvant chemotherapy; patients in cohort D received WT1-immunotherapeutic in an open-label manner
Fig. 2
Fig. 2
Pre- and post-immunization WT1-specific antibody titers in patients from a cohort A, b cohort B, c cohort C, and d cohort D (ATP cohort for immunogenicity). ATP according-to-protocol; EU/ml, ELISA units per ml (antibody concentration). The cut-off of the ELISA assay was 9 EU/ml. The color lines correspond to individual patients’ antibody titers at indicated timepoints

References

    1. Mahoney KM, Freeman GJ, McDermott DF. The next immune-checkpoint inhibitors: PD-1/PD-L1 Blockade in Melanoma. Clin Ther. 2015;37(4):764–782. doi: 10.1016/j.clinthera.2015.02.018.
    1. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH, Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. 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. Lancet Oncol. 2015;16(4):375–384. doi: 10.1016/S1470-2045(15)70076-8.
    1. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–133. doi: 10.1056/NEJMoa1302369.
    1. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu LA, Waxman IM, Sharma P, CheckMate I. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813. doi: 10.1056/NEJMoa1510665.
    1. Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology. 2015;29(5):375–385.
    1. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016
    1. Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol. 2009;27(35):5911–5918. doi: 10.1200/JCO.2009.23.3494.
    1. Sugiyama H. WT1 (Wilms’ tumor gene 1): biology and cancer immunotherapy. Jpn J Clin Oncol. 2010;40(5):377–387. doi: 10.1093/jjco/hyp194.
    1. Nishida S, Koido S, Takeda Y, Homma S, Komita H, Takahara A, Morita S, Ito T, Morimoto S, Hara K, Tsuboi A, Oka Y, Yanagisawa S, Toyama Y, Ikegami M, Kitagawa T, Eguchi H, Wada H, Nagano H, Nakata J, Nakae Y, Hosen N, Oji Y, Tanaka T, Kawase I, Kumanogoh A, Sakamoto J, Doki Y, Mori M, Ohkusa T, Tajiri H, Sugiyama H. Wilms tumor gene (WT1) peptide-based cancer vaccine combined with gemcitabine for patients with advanced pancreatic cancer. J Immunother. 2014;37(2):105–114. doi: 10.1097/CJI.0000000000000020.
    1. Perugorria MJ, Castillo J, Latasa MU, Goni S, Segura V, Sangro B, Prieto J, Avila MA, Berasain C. Wilms’ tumor 1 gene expression in hepatocellular carcinoma promotes cell dedifferentiation and resistance to chemotherapy. Cancer Res. 2009;69(4):1358–1367. doi: 10.1158/0008-5472.CAN-08-2545.
    1. Qi XW, Zhang F, Wu H, Liu JL, Zong BG, Xu C, Jiang J. Wilms’ tumor 1 (WT1) expression and prognosis in solid cancer patients: a systematic review and meta-analysis. Sci Rep. 2015;5:8924. doi: 10.1038/srep08924.
    1. Gillmore R, Xue SA, Holler A, Kaeda J, Hadjiminas D, Healy V, Dina R, Parry SC, Bellantuono I, Ghani Y, Coombes RC, Waxman J, Stauss HJ. Detection of Wilms’ tumor antigen–specific CTL in tumor-draining lymph nodes of patients with early breast cancer. Clin Cancer Res. 2006;12(1):34–42. doi: 10.1158/1078-0432.CCR-05-1483.
    1. Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323–5337. doi: 10.1158/1078-0432.CCR-09-0737.
    1. Caldon CE, Lee CS, Sutherland RL, Musgrove EA. Wilms’ tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation. Oncogene. 2008;27(1):126–138. doi: 10.1038/sj.onc.1210622.
    1. Qi XW, Zhang F, Yang XH, Fan LJ, Zhang Y, Liang Y, Ren L, Zhong L, Chen QQ, Zhang KY, Zang WD, Wang LS, Zhang Y, Jiang J. High Wilms’ tumor 1 mRNA expression correlates with basal-like and ERBB2 molecular subtypes and poor prognosis of breast cancer. Oncol Rep. 2012;28(4):1231–1236.
    1. Tuna M, Chavez-Reyes A, Tari AM. HER2/neu increases the expression of Wilms’ Tumor 1 (WT1) protein to stimulate S-phase proliferation and inhibit apoptosis in breast cancer cells. Oncogene. 2005;24(9):1648–1652. doi: 10.1038/sj.onc.1208345.
    1. Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y, Tamaki H, Sugiyama H, Noguchi S. High expression of Wilms’ tumor suppressor gene predicts poor prognosis in breast cancer patients. Clin Cancer Res. 2002;8(5):1167–1171.
    1. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003;12(5):320–327. doi: 10.1016/S0960-9776(03)00106-1.
    1. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS. 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(27):2959–2966. doi: 10.1200/JCO.2013.55.0491.
    1. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, Earl HM, Poole CJ, Hiller L, Dunn JA, Bowden SJ, Twelves C, Bartlett JM, Mahmoud SM, Rakha E, Ellis IO, Liu S, Gao D, Nielsen TO, Pharoah PD, Caldas C. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25(8):1536–1543. doi: 10.1093/annonc/mdu191.
    1. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C. 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(8):1544–1550. doi: 10.1093/annonc/mdu112.
    1. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 2003;21:807–839. doi: 10.1146/annurev.immunol.21.120601.141135.
    1. Apetoh L, Tesniere A, Ghiringhelli F, Kroemer G, Zitvogel L. Molecular interactions between dying tumor cells and the innate immune system determine the efficacy of conventional anticancer therapies. Cancer Res. 2008;68(11):4026–4030. doi: 10.1158/0008-5472.CAN-08-0427.
    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(1):15–25. doi: 10.1038/cdd.2013.67.
    1. Proietti E, Moschella F, Capone I, Belardelli F. Exploitation of the propulsive force of chemotherapy for improving the response to cancer immunotherapy. Mol Oncol. 2012;6(1):1–14. doi: 10.1016/j.molonc.2011.11.005.
    1. Wijayahadi N, Haron MR, Stanslas J, Yusuf Z. Changes in cellular immunity during chemotherapy for primary breast cancer with anthracycline regimens. J Chemother. 2007;19(6):716–723. doi: 10.1179/joc.2007.19.6.716.
    1. del Giglio A, Eniu A, Ganea-Motan D, Topuzov E, Lubenau H. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer. 2008;8:332. doi: 10.1186/1471-2407-8-332.
    1. Kurtin S. Myeloid toxicity of cancer treatment. J Adv Pract Oncol. 2012;3(4):209–224.
    1. Rivera E, Smith RE., Jr Trends in recommendations of myelosuppressive chemotherapy for the treatment of breast cancer: evolution of the national comprehensive cancer network guidelines and the cooperative group studies. Clin Breast Cancer. 2006;7(1):33–41. doi: 10.3816/CBC.2006.n.011.
    1. Kandalaft LE, Singh N, Liao JB, Facciabene A, Berek JS, Powell DJ, Jr, Coukos G. The emergence of immunomodulation: combinatorial immunochemotherapy opportunities for the next decade. Gynecol Oncol. 2010;116(2):222–233. doi: 10.1016/j.ygyno.2009.11.001.
    1. Emens LA. Chemoimmunotherapy. Cancer J. 2010;16(4):295–303. doi: 10.1097/PPO.0b013e3181eb5066.
    1. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11(3):215–233. doi: 10.1038/nrd3626.
    1. Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39(1):74–88. doi: 10.1016/j.immuni.2013.06.014.
    1. Demaria S, Volm MD, Shapiro RL, Yee HT, Oratz R, Formenti SC, Muggia F, Symmans WF. Development of tumor-infiltrating lymphocytes in breast cancer after neoadjuvant paclitaxel chemotherapy. Clin Cancer Res. 2001;7(10):3025–3030.
    1. Hornychova H, Melichar B, Tomsova M, Mergancova J, Urminska H, Ryska A. Tumor-infiltrating lymphocytes predict response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer Investig. 2008;26(10):1024–1031. doi: 10.1080/07357900802098165.
    1. Jones KL, Buzdar AU. Evolving novel anti-HER2 strategies. Lancet Oncol. 2009;10(12):1179–1187. doi: 10.1016/S1470-2045(09)70315-8.
    1. Minami T, Kijima T, Kohmo S, Arase H, Otani Y, Nagatomo I, Takahashi R, Miyake K, Higashiguchi M, Morimura O, Ihara S, Tsujino K, Hirata H, Inoue K, Takeda Y, Kida H, Tachibana I, Kumanogoh A. Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis. Sci Rep. 2013;3:2669. doi: 10.1038/srep02669.
    1. Knutson KL, Disis ML. Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother. 2005;54(8):721–728. doi: 10.1007/s00262-004-0653-2.
    1. Wang J, Zhang Q, Jin S, Feng M, Kang X, Zhao S, Liu S, Zhao W. Immoderate inhibition of estrogen by anastrozole enhances the severity of experimental polyarthritis. Exp Gerontol. 2009;44(6–7):398–405.
    1. Pujol JL, Vansteenkiste JF, De Pas TM, Atanackovic D, Reck M, Thomeer M, Douillard JY, Fasola G, Potter V, Taylor P, Bosquee L, Scheubel R, Jarnjak S, Debois M, de Sousa Alves P, Louahed J, Brichard VG, Lehmann FF. Safety and Immunogenicity of MAGE-A3 Cancer Immunotherapeutic with or without Adjuvant Chemotherapy in Patients with Resected Stage IB to III MAGE-A3-Positive Non-Small-Cell Lung Cancer. J Thorac Oncol. 2015;10(10):1458–1467. doi: 10.1097/JTO.0000000000000653.

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