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Open Access 01-01-2019 | Original Article

An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells

Authors: Michele Tomasicchio, Lynn Semple, Aliasgar Esmail, Richard Meldau, Philippa Randall, Anil Pooran, Malika Davids, Lydia Cairncross, David Anderson, Jennifer Downs, Francois Malherbe, Nicolas Novitzky, Eugenio Panieri, Suzette Oelofse, Rolanda Londt, Thurandrie Naiker, Keertan Dheda

Published in: Cancer Immunology, Immunotherapy | Issue 1/2019

Abstract

Breast cancer remains one of the leading causes of cancer-associated death worldwide. Conventional treatment is associated with substantial toxicity and suboptimal efficacy. We, therefore, developed and evaluated the in vitro efficacy of an autologous dendritic cell (DC) vaccine to treat breast cancer. We recruited 12 female patients with stage 1, 2, or 3 breast cancer and matured their DCs with autologous tumour-specific lysate, a toll-like receptor (TLR)-3 and 7/8 agonist, and an interferon-containing cocktail. The efficacy of the vaccine was evaluated by its ability to elicit a cytotoxic T-lymphocyte response to autologous breast cancer cells in vitro. Matured DCs (≥ 60% upregulation of CD80, CD86, CD83, and CCR7) produced high levels of the Th1 effector cytokine, IL12-p70 (1.2 ng/ml; p < 0.0001), compared to DCs pulsed with tumour lysate, or matured with an interferon-containing cocktail alone. We further showed that matured DCs enhance antigen-specific CD8 + T-cell responses to HER-2 (4.5%; p < 0.005) and MUC-1 (19%; p < 0.05) tetramers. The mature DCs could elicit a robust and dose-dependent antigen-specific cytotoxic T-lymphocyte response (65%) which was tumoricidal to autologous breast cancer cells in vitro compared to T-lymphocytes that were primed with autologous lysate loaded-DCs (p < 0.005). Lastly, we showed that the mature DCs post-cryopreservation maintained high viability, maintained their mature phenotype, and remained free of endotoxins or mycoplasma. We have developed a DC vaccine that is cytotoxic to autologous breast cancer cells in vitro. The tools and technology generated here will now be applied to a phase I/IIa clinical trial.

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World Health Organisation (2015) Cancer Fact Sheet. http://www.who.int/mediacentre/factsheets/fs297/en/. Assessed 9 November 2016

American Cancer Society (2017) Cancer Facts and Figures. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. Assessed 27 October 2017

Breast cancer stages (2018) http://www.breastcancer.org/symptoms/diagnosis/staging. Assessed 5 June 2018

Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258CrossRefPubMed

Schadendorf D, Ugurel S, Schuler-Thurner B et al (2006) Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 17: 563–570. https://doi.org/10.1093/annonc/mdj138 CrossRefPubMed

Draube A, Klein-Gonzalez N, Mattheus S, Brillant C, Hellmich M, Engert A, von Bergwelt-Baildon M (2011) Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis. PloS one 6 (4) e18801. https://doi.org/10.1371/journal.pone.0018801 CrossRefPubMedPubMedCentral

Oh T, Sayegh ET, Fakurnejad S, Oyon D, Lamano JB, DiDomenico JD, Bloch O, Parsa AT (2015) Vaccine therapies in malignant glioma. Curr Neurol Neurosci Rep 15 (1): 508. https://doi.org/10.1007/s11910-014-0508-y CrossRefPubMedPubMedCentral

Adams M, Navabi H, Jasani B, Man S, Fiander A, Evans AS, Donninger C, Mason M (2003) Dendritic cell (DC) based therapy for cervical cancer: use ofDC pulsed with tumour lysate and matured with a novel synthetic clinically non-toxic double stranded RNA analogue poly [I]:poly [C(12)U] (Ampligen R). Vaccine 21(7–8):787–790. https://doi.org/10.1016/S0264-410X(02)00599-6 CrossRefPubMed

Gorden KB, Gorski KS, Gibson SJ, Kedl RM, Kieper WC, Qiu X, Tomai MA, Alkan SS, Vasilakos JP (2005) Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol 174:1259–1268. https://doi.org/10.4049/jimmunol.174.3.1259 CrossRefPubMed

10.

Michiels A, Breckpot K, Corthals J, Tuyaerts S, Bonehill A, Heirman C, Thielemans K, Aerts JL (2006) Induction of antigen-specific CD8 + cytotoxic T cells by dendritic cells co-electroporated with a dsRNA analogue and tumor antigen mRNA. Gene Ther 13:1027–1036. https://doi.org/10.1038/sj.gt.3302750 CrossRefPubMed

11.

Kalinski P, Muthuswamy R, Urban J (2013) Dendritic cells in cancer immunotherapy: vaccines and combination immunotherapies. Expert Rev Vaccines 12: 285–295. https://doi.org/10.1586/erv.13.22 CrossRefPubMedPubMedCentral

12.

Carreno BM, Becker-Hapak M, Huang A et al (2013) IL-12p70-producing patient DC vaccine elicits Tc1-polarized immunity. J Clin Invest 123:3383–3394. https://doi.org/10.1172/JCI68395 CrossRefPubMedPubMedCentral

13.

DeBenedette MA, Calderhead DM, Tcherepanova IY, Nicolette CA, Healey DG (2011) Potency of mature CD40L RNA electroporated dendritic cells correlates with IL-12 secretion by tracking multifunctional CD8(+)/CD28(+) cytotoxic T-cell responses in vitro. J Immunother 34: 45–57. https://doi.org/10.1097/CJI.0b013e3181fb651a CrossRefPubMed

14.

Okada H, Kalinski P, Ueda R et al (2011) Induction of CD8 + T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol 29:330–336. https://doi.org/10.1200/JCO.2010.30.7744 CrossRefPubMed

15.

Corthay A, Skovseth DK, Lundin KU, Rosjo E, Omholt H, Hofgaard PO, Haraldsen G, Bogen B (2005) Primary antitumor immune response mediated by CD4 + T cells. Immunity 22: 371–383. https://doi.org/10.1016/j.immuni.2005.02.003 CrossRefPubMed

16.

Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12: 265–277. https://doi.org/10.1038/nrc3258 CrossRefPubMedPubMedCentral

17.

Quezada SA, Simpson TR, Peggs KS et al (2010) Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207: 637–650. https://doi.org/10.1084/jem.20091918 CrossRefPubMedPubMedCentral

18.

Pauletti G, Godolphin W, Press MF, Slamon DJ (1996) Detection and quantitation of HER-2/neu gene amplification in human breast cancer archival material using fluorescence in situ hybridization. Oncogene 13:63–72PubMed

19.

Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23: 41–46. https://doi.org/10.1038/12640 CrossRefPubMed

20.

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235: 177–182. https://doi.org/10.1126/science.3798106 CrossRefPubMed

21.

Subik K, Lee JF, Baxter L et al (2010) The expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer (Auckl) 4:35–41PubMedCentral

22.

Jones KL, Anderson NS, Addison J (1978) Glucocorticoid-induced growth inhibition of cells from a human lung alveolar cell carcinoma. Cancer Res 38:1688–1693PubMed

23.

Ramalingam A, Hirai A, Thompson EA (1997) Glucocorticoid inhibition of fibroblast proliferation and regulation of the cyclin kinase inhibitor p21Cip1. Mol Endocrinol 11: 577–586. https://doi.org/10.1210/mend.11.5.9923 CrossRefPubMed

24.

Koido S, Hara E, Homma S et al (2010) Dendritic/pancreatic carcinoma fusions for clinical use: Comparative functional analysis of healthy- versus patient-derived fusions. Clin Immunol 135:384–400. https://doi.org/10.1016/j.clim.2010.02.003 CrossRefPubMed

25.

Curtsinger JM, Schmidt CS, Mondino A, Lins DC, Kedl RM, Jenkins MK, Mescher MF (1999) Inflammatory cytokines provide a third signal for activation of naive CD4 + and CD8 + T cells. J Immunol 162:3256–3262PubMed

26.

Schmidt CS, Mescher MF (1999) Adjuvant effect of IL-12: conversion of peptide antigen administration from tolerizing to immunizing for CD8 + T cells in vivo. J Immunol 163:2561–2567PubMed

27.

Xiao Z, Casey KA, Jameson SC, Curtsinger JM, Mescher MF (2009) Programming for CD8 T cell memory development requires IL-12 or type I IFN. J Immunol 182:2786–2794. https://doi.org/10.4049/jimmunol.0803484 CrossRefPubMed

28.

Sabado RL, Balan S, Bhardwaj N (2017) Dendritic cell-based immunotherapy. Cell Res 27: 74–95. https://doi.org/10.1038/cr.2016.157 CrossRefPubMed

29.

Nicodemus CF, Wang L, Lucas J, Varghese B, Berek JS (2010) Toll-like receptor-3 as a target to enhance bioactivity of cancer immunotherapy. Am J Obstet Gynecol 202:608. https://doi.org/10.1016/j.ajog.2009.12.001 CrossRefPubMed

30.

Warger T, Osterloh P, Rechtsteiner G, Fassbender M, Heib V, Schmid B, Schmitt E, Schild H, Radsak MP (2006) Synergistic activation of dendritic cells by combined Toll-like receptor ligation induces superior CTL responses in vivo. Blood 108: 544–550. https://doi.org/10.1182/blood-2005-10-4015 CrossRefPubMed

31.

Okada N, Mori N, Koretomo R et al (2005) Augmentation of the migratory ability of DC-based vaccine into regional lymph nodes by efficient CCR7 gene transduction. Gene Ther 12: 129–139. https://doi.org/10.1038/sj.gt.3302358 CrossRefPubMed

32.

Lotze MT (1997) Getting to the source: dendritic cells as therapeutic reagents for the treatment of patients with cancer. Ann Surg 226:1–5CrossRefPubMedPubMedCentral

33.

Dekaban GA, Hamilton AM, Fink CA, Au B, de Chickera SN, Ribot EJ, Foster PJ (2013) Tracking and evaluation of dendritic cell migration by cellular magnetic resonance imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:469–83. https://doi.org/10.1002/wnan.1227 CrossRefPubMed

34.

Mosca PJ, Hobeika AC, Clay TM, Nair SK, Thomas EK, Morse MA, Lyerly HK (2000) A subset of human monocyte-derived dendritic cells expresses high levels of interleukin-12 in response to combined CD40 ligand and interferon-gamma treatment. Blood 96:3499–3504PubMed

35.

Navabi H, Jasani B, Reece A, Clayton A, Tabi Z, Donninger C, Mason M, Adams M (2009) A clinical grade poly I:C-analogue (Ampligen) promotes optimal DC maturation and Th1-type T cell responses of healthy donors and cancer patients in vitro. Vaccine 27: 107–115. https://doi.org/10.1016/j.vaccine.2008.10.024 CrossRefPubMed

36.

Lee M, Park CS, Lee YR, Im SA, Song S, Lee CK (2014) Resiquimod, a TLR7/8 agonist, promotes differentiation of myeloid-derived suppressor cells into macrophages and dendritic cells. Arch Pharm Res 37: 1234–1240. https://doi.org/10.1007/s12272-014-0379-4 CrossRefPubMed

37.

Neller MA, Lopez JA, Schmidt CW (2008) Antigens for cancer immunotherapy. Semin Immunol 20: 286–295. https://doi.org/10.1016/j.smim.2008.09.006 CrossRefPubMed

38.

Benteyn D, Heirman C, Bonehill A, Thielemans K, Breckpot K (2015) mRNA-based dendritic cell vaccines. Expert Rev Vaccines 14: 161–176. https://doi.org/10.1586/14760584.2014.957684 CrossRefPubMed

39.

Curtsinger JM, Johnson CM, Mescher MF (2003) CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J Immunol 171:5165–5171CrossRefPubMed

40.

Lee JJ, Foon KA, Mailliard RB, Muthuswamy R, Kalinski P (2008) Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia. J Leukoc Biol 84: 319–325. https://doi.org/10.1189/jlb.1107737 CrossRefPubMedPubMedCentral

41.

Mailliard RB, Wankowicz-Kalinska A, Cai Q, Wesa A, Hilkens CM, Kapsenberg ML, Kirkwood JM, Storkus WJ, Kalinski P (2004) Alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res 64:5934–5937. https://doi.org/10.1158/0008-5472.CAN-04-1261 CrossRefPubMed

42.

Xu S, Koski GK, Faries M, Bedrosian I, Mick R, Maeurer M, Cheever MA, Cohen PA, Czerniecki BJ (2003) Rapid high efficiency sensitization of CD8 + T cells to tumor antigens by dendritic cells leads to enhanced functional avidity and direct tumor recognition through an IL-12-dependent mechanism. J Immunol 171:2251–2261CrossRefPubMed

43.

Gustafsson K, Ingelsten M, Bergqvist L, Nystrom J, Andersson B, Karlsson-Parra A (2008) Recruitment and activation of natural killer cells in vitro by a human dendritic cell vaccine. Cancer Res 68:5965–5971. https://doi.org/10.1158/0008-5472.CAN-07-6494 CrossRefPubMed

44.

Watchmaker PB, Urban JA, Berk E, Nakamura Y, Mailliard RB, Watkins SC, van Ham SM, Kalinski P (2008) Memory CD8 + T cells protect dendritic cells from CTL killing. J Immunol 180:3857–3865CrossRefPubMed

Title: An autologous dendritic cell vaccine polarizes a Th-1 response which is tumoricidal to patient-derived breast cancer cells
Authors: Michele Tomasicchio
Lynn Semple
Aliasgar Esmail
Richard Meldau
Philippa Randall
Anil Pooran
Malika Davids
Lydia Cairncross
David Anderson
Jennifer Downs
Francois Malherbe
Nicolas Novitzky
Eugenio Panieri
Suzette Oelofse
Rolanda Londt
Thurandrie Naiker
Keertan Dheda
Publication date: 01-01-2019
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 1/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-018-2238-5

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