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Cancer Immunology, Immunotherapy

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10.11.2017 | Original Article

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

verfasst von: Bai-Le Zuo, Bo Yan, Guo-Xu Zheng, Wen-Jin Xi, Xiao Zhang, An-Gang Yang, Lin-Tao Jia

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 3/2018

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Abstract

Chimeric antigen receptor-modulated T lymphocytes (CAR-T) have emerged as a powerful tool for arousing anticancer immunity. Endogenous ligands for tumor antigen may outperform single-chain variable fragments to serve as a component of CARs with high cancer recognition efficacy and minimized immunogenicity. As heterodimerization and signaling partners for human epidermal growth factor receptor 2 (HER2), HER3/HER4 has been implicated in tumorigenic signaling and therapeutic resistance of breast cancer. In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR-T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG1β-based CAR-T cells effectively suppress breast cancer driven by HER family receptors, and may provide a novel strategy to overcome cancer resistance to HER2-targeted therapy.

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Kochenderfer JN, Rosenberg SA (2013) Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol 10(5):267–276. https://doi.org/10.1038/nrclinonc.2013.46 CrossRefPubMed

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–1518. https://doi.org/10.1056/NEJMoa1215134 CrossRefPubMedPubMedCentral

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517. https://doi.org/10.1056/NEJMoa1407222 CrossRefPubMedPubMedCentral

Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, Fry TJ, Orentas R, Sabatino M, Shah NN, Steinberg SM, Stroncek D, Tschernia N, Yuan C, Zhang H, Zhang L, Rosenberg SA, Wayne AS, Mackall CL (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385(9967):517–528. https://doi.org/10.1016/s0140-6736(14)61403-3 CrossRefPubMed

Gilham DE, Debets R, Pule M, Hawkins RE, Abken H (2012) CAR-T cells and solid tumors: tuning T cells to challenge an inveterate foe. Trends Mol Med 18(7):377–384. https://doi.org/10.1016/j.molmed.2012.04.009 CrossRefPubMed

Posey AD Jr, Schwab RD, Boesteanu AC, Steentoft C, Mandel U, Engels B, Stone JD, Madsen TD, Schreiber K, Haines KM, Cogdill AP, Chen TJ, Song D, Scholler J, Kranz DM, Feldman MD, Young R, Keith B, Schreiber H, Clausen H, Johnson LA, June CH (2016) Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane mucin MUC1 control adenocarcinoma. Immunity 44(6):1444–1454. https://doi.org/10.1016/j.immuni.2016.05.014 CrossRefPubMedPubMedCentral

Burga RA, Thorn M, Point GR, Guha P, Nguyen CT, Licata LA, DeMatteo RP, Ayala A, Espat NJ, Junghans RP, Katz SC (2015) Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T. Cancer Immunol Immunother 64(7):817–829. https://doi.org/10.1007/s00262-015-1692-6 CrossRefPubMedPubMedCentral

Dai H, Wang Y, Lu X, Han W (2016) Chimeric antigen receptors modified T-cells for cancer therapy. J Natl Cancer Inst 108(7). https://doi.org/10.1093/jnci/djv439

Fesnak AD, June CH, Levine BL (2016) Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16(9):566–581. https://doi.org/10.1038/nrc.2016.97 CrossRefPubMedPubMedCentral

10.

Srivastava S, Riddell SR (2015) Engineering CAR-T cells: design concepts. Trends Immunol 36(8):494–502. https://doi.org/10.1016/j.it.2015.06.004 CrossRefPubMedPubMedCentral

11.

Hammill JA, VanSeggelen H, Helsen CW, Denisova GF, Evelegh C, Tantalo DG, Bassett JD, Bramson JL (2015) Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J Immunother Cancer 3:55. https://doi.org/10.1186/s40425-015-0099-4 CrossRefPubMedPubMedCentral

12.

Breuleux M (2007) Role of heregulin in human cancer. Cell Mol Life Sci 64(18):2358–2377. https://doi.org/10.1007/s00018-007-7120-0 CrossRefPubMed

13.

Batlevi CL, Matsuki E, Brentjens RJ, Younes A (2016) Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol 13(1):25–40. https://doi.org/10.1038/nrclinonc.2015.187 CrossRefPubMed

14.

Khalil DN, Smith EL, Brentjens RJ, Wolchok JD (2016) The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13(5):273–290. https://doi.org/10.1038/nrclinonc.2016.25 CrossRefPubMedPubMedCentral

15.

Bachireddy P, Burkhardt UE, Rajasagi M, Wu CJ (2015) Haematological malignancies: at the forefront of immunotherapeutic innovation. Nat Rev Cancer 15(4):201–215. https://doi.org/10.1038/nrc3907 CrossRefPubMedPubMedCentral

16.

Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K, Davidoff AM, Chng WJ, Campana D (2014) T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res 74(1):93–103. https://doi.org/10.1158/0008-5472.CAN-13-1365 CrossRefPubMed

17.

Scott AM, Wolchok JD, Old LJ (2012) Antibody therapy of cancer. Nat Rev Cancer 12(4):278–287. https://doi.org/10.1038/nrc3236 CrossRefPubMed

18.

Vanneman M, Dranoff G (2012) Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer 12(4):237–251. https://doi.org/10.1038/nrc3237 CrossRefPubMedPubMedCentral

19.

De Keulenaer GW, Doggen K, Lemmens K (2010) The vulnerability of the heart as a pluricellular paracrine organ: lessons from unexpected triggers of heart failure in targeted ErbB2 anticancer therapy. Circ Res 106(1):35–46. https://doi.org/10.1161/CIRCRESAHA.109.205906 CrossRefPubMed

20.

Hegde M, Mukherjee M, Grada Z, Pignata A, Landi D, Navai SA, Wakefield A, Fousek K, Bielamowicz K, Chow KK, Brawley VS, Byrd TT, Krebs S, Gottschalk S, Wels WS, Baker ML, Dotti G, Mamonkin M, Brenner MK, Orange JS, Ahmed N (2016) Tandem CAR T cells targeting HER2 and IL13Ralpha2 mitigate tumor antigen escape. J Clin Invest 126(8):3036–3052. https://doi.org/10.1172/JCI83416 CrossRefPubMedPubMedCentral

21.

Wilson TR, Lee DY, Berry L, Shames DS, Settleman J (2011) Neuregulin-1-mediated autocrine signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. Cancer Cell 20(2):158–172. https://doi.org/10.1016/j.ccr.2011.07.011 CrossRefPubMed

22.

Odiete O, Hill MF, Sawyer DB (2012) Neuregulin in cardiovascular development and disease. Circ Res 111(10):1376–1385. https://doi.org/10.1161/CIRCRESAHA.112.267286 CrossRefPubMedPubMedCentral

23.

Willem M (2016) Proteolytic processing of neuregulin-1. Brain Res Bull 126(Pt 2):178–182. https://doi.org/10.1016/j.brainresbull.2016.07.003 CrossRefPubMed

24.

Altenschmidt U, Kahl R, Moritz D, Schnierle BS, Gerstmayer B, Wels W, Groner B (1996) Cytolysis of tumor cells expressing the Neu/erbB-2, erbB-3, and erbB-4 receptors by genetically targeted naive T lymphocytes. Clin Cancer Res 2(6):11

25.

Muniappan ABB, Lebkowski J, Talib S (2000) Ligand-mediated cytolysis of tumor cells: use of heregulin-zeta chimeras to redirect cytotoxic T lymphocytes. Cancer Gene Ther 7(1):128–134CrossRefPubMed

26.

Amin DN, Campbell MR, Moasser MM (2010) The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol 21(9):944–950. https://doi.org/10.1016/j.semcdb.2010.08.007 CrossRefPubMedPubMedCentral

27.

Davies DM, Foster J, Van Der Stegen SJ, Parente-Pereira AC, Chiapero-Stanke L, Delinassios GJ, Burbridge SE, Kao V, Liu Z, Bosshard-Carter L, Van Schalkwyk MC, Box C, Eccles SA, Mather SJ, Wilkie S, Maher J (2012) Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells. Mol Med 18:565–576. https://doi.org/10.2119/molmed.2011.00493 CrossRefPubMedPubMedCentral

28.

Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, Walker WJ, McNally KA, Lim WA (2016) Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167(2):419–432.e416. https://doi.org/10.1016/j.cell.2016.09.011 CrossRefPubMedPubMedCentral

29.

Sackstein R, Schatton T, Barthel SR (2017) T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab Invest 97(6):669–697. https://doi.org/10.1038/labinvest.2017.25 CrossRefPubMedPubMedCentral

Titel: Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor
verfasst von: Bai-Le Zuo
Bo Yan
Guo-Xu Zheng
Wen-Jin Xi
Xiao Zhang
An-Gang Yang
Lin-Tao Jia
Publikationsdatum: 10.11.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Immunology, Immunotherapy / Ausgabe 3/2018
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-2089-5

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23.04.2024 | Medikamente in Schwangerschaft und Stillzeit | Nachrichten

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor

Abstract

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ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

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Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

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