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BMC Cancer
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies

Authors: Ian M Zitron, Archana Thakur, Oxana Norkina, Geoffrey R Barger, Lawrence G Lum, Sandeep Mittal

Published in: BMC Cancer | Issue 1/2013

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Abstract

Background

Since most glioblastomas express both wild-type EGFR and EGFRvIII as well as HER2/neu, they are excellent targets for activated T cells (ATC) armed with bispecific antibodies (BiAbs) that target EGFR and HER2.

Methods

ATC were generated from PBMC activated for 14 days with anti-CD3 monoclonal antibody in the presence of interleukin-2 and armed with chemically heteroconjugated anti-CD3×anti-HER2/neu (HER2Bi) and/or anti-CD3×anti-EGFR (EGFRBi). HER2Bi- and/or EGFRBi-armed ATC were examined for in vitro cytotoxicity using MTT and 51Cr-release assays against malignant glioma lines (U87MG, U118MG, and U251MG) and primary glioblastoma lines.

Results

EGFRBi-armed ATC killed up to 85% of U87, U118, and U251 targets at effector:target ratios (E:T) ranging from 1:1 to 25:1. Engagement of tumor by EGFRBi-armed ATC induced Th1 and Th2 cytokine secretion by armed ATC. HER2Bi-armed ATC exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative U87 cells. HER2Bi- or EGFRBi-armed ATC exhibited 50—80% cytotoxicity against four primary glioblastoma lines as well as a temozolomide (TMZ)-resistant variant of U251. Both CD133– and CD133+ subpopulations were killed by armed ATC. Targeting both HER2Bi and EGFRBi simultaneously showed enhanced efficacy than arming with a single BiAb. Armed ATC maintained effectiveness after irradiation and in the presence of TMZ at a therapeutic concentration and were capable of killing multiple targets.

Conclusion

High-grade gliomas are suitable for specific targeting by armed ATC. These data, together with additional animal studies, may provide the preclinical support for the use of armed ATC as a valuable addition to current treatment regimens.
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Literature
1.
Dolecek TA, Propp JM, Stroup NE, Kruchko C: CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. Neuro Oncol. 2012, 14 (5): v1-49. 10.1093/neuonc/nos218.CrossRefPubMedPubMedCentral
2.
Weiner LM, Clark JI, Davey M, Li WS, Ring DB, Alpaugh RK, Garcia de Palazzo I: Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. Cancer Res. 1995, 55: 4586-4593.PubMed
3.
Ren-Heidenreich L, Davol PA, Kouttab NM, Elfenbein GJ, Lum LG: Redirected T-cell cytotoxicity to epithelial cell adhesion molecule-overexpressing adenocarcinomas by a novel recombinant antibody, E3Bi, in vitro and in an animal model. Cancer. 2004, 100: 1095-1103. 10.1002/cncr.20060.CrossRefPubMed
4.
Reusch U, Sundaram M, Davol PA, Olson SD, Davis JB, Demel K, Nissim J, Rathore R, Liu PY, Lum LG: Anti-CD3 x anti-epidermal growth factor receptor (EGFR) bispecific antibody redirects T-cell cytolytic activity to EGFR-positive cancers in vitro and in an animal model. Clin Cancer Res. 2006, 12: 183-190. 10.1158/1078-0432.CCR-05-1855.CrossRefPubMed
5.
Chan JK, Hamilton CA, Cheung MK, Karimi M, Baker J, Gall JM, Schulz S, Thorne SH, Teng NN, Contag CH: Enhanced killing of primary ovarian cancer by retargeting autologous cytokine-induced killer cells with bispecific antibodies: a preclinical study. Clin Cancer Res. 2006, 12: 1859-1867. 10.1158/1078-0432.CCR-05-2019.CrossRefPubMed
6.
Sen M, Wankowski DM, Garlie NK, Siebenlist RE, Van Epps D, LeFever AV, Lum LG: Use of anti-CD3 x anti-HER2/neu bispecific antibody for redirecting cytotoxicity of activated T cells toward HER2/neu+ tumors. J Hematother Stem Cell Res. 2001, 10: 247-260. 10.1089/15258160151134944.CrossRefPubMed
7.
Gall JM, Davol PA, Grabert RC, Deaver M, Lum LG: T cells armed with anti-CD3 x anti-CD20 bispecific antibody enhance killing of CD20+ malignant B cells and bypass complement-mediated rituximab resistance in vitro. Exp Hematol. 2005, 33: 452-459. 10.1016/j.exphem.2005.01.007.CrossRefPubMed
8.
Lum HE, Miller M, Davol PA, Grabert RC, Davis JB, Lum LG: Preclinical studies comparing different bispecific antibodies for redirecting T cell cytotoxicity to extracellular antigens on prostate carcinomas. Anticancer Res. 2005, 25: 43-52.PubMed
9.
Yankelevich M, Kondadasula SV, Thakur A, Buck S, Cheung NK, Lum LG: Anti-CD3 x anti-GD2 bispecific antibody redirects T-cell cytolytic activity to neuroblastoma targets. Pediatr Blood Cancer. 2012, 59: 1198-1205. 10.1002/pbc.24237.CrossRefPubMedPubMedCentral
10.
Grabert RC, Cousens LP, Smith JA, Olson S, Gall J, Young WB, Davol PA, Lum LG: Human T cells armed with Her2/neu bispecific antibodies divide, are cytotoxic, and secrete cytokines with repeated stimulation. Clin Cancer Res. 2006, 12: 569-576. 10.1158/1078-0432.CCR-05-2005.CrossRefPubMed
11.
Davol PA, Smith JA, Kouttab N, Elfenbein GJ, Lum LG: Anti-CD3 x anti-HER2 bispecific antibody effectively redirects armed T cells to inhibit tumor development and growth in hormone-refractory prostate cancer-bearing severe combined immunodeficient beige mice. Clin Prostate Cancer. 2004, 3: 112-121.CrossRefPubMed
12.
Nitta T, Sato K, Yagita H, Okumura K, Ishii S: Preliminary trial of specific targeting therapy against malignant glioma. Lancet. 1990, 335: 368-371. 10.1016/0140-6736(90)90205-J.CrossRefPubMed
13.
Yuan X, Curtin J, Xiong Y, Liu G, Waschsmann-Hogiu S, Farkas DL, Black KL, Yu JS: Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene. 2004, 23: 9392-9400. 10.1038/sj.onc.1208311.CrossRefPubMed
14.
Lum LG, Ramesh M, Thakur A, Mitra S, Deol A, Uberti JP, Pellett PE: Targeting cytomegalovirus-infected cells using T cells armed with anti-CD3 x anti-CMV bispecific antibody. Biol Blood Marrow Transplant. 2012, 18: 1012-1022. 10.1016/j.bbmt.2012.01.022.CrossRefPubMedPubMedCentral
15.
Thakur A, Norkina O, Lum LG: In vitro synthesis of primary specific anti-breast cancer antibodies by normal human peripheral blood mononuclear cells. Cancer Immunol Immunother. 2011, 60: 1707-1720. 10.1007/s00262-011-1056-9.CrossRefPubMedPubMedCentral
16.
Thakur A, Lum LG: Cancer therapy with bispecific antibodies: Clinical experience. Curr Opin Mol Ther. 2010, 12: 340-349.PubMedPubMedCentral
17.
Thakur A, Lum LG, Schalk D, Azmi A, Banerjee S, Sarkar FH, Mohommad R: Pan-Bcl-2 inhibitor AT-101 enhances tumor cell killing by EGFR targeted T cells. PLoS One. 2012, 7: e47520-10.1371/journal.pone.0047520.CrossRefPubMedPubMedCentral
18.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF: Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003, 100: 3983-3988. 10.1073/pnas.0530291100.CrossRefPubMedPubMedCentral
19.
Singh SK, Clarke ID, Hide T, Dirks PB: Cancer stem cells in nervous system tumors. Oncogene. 2004, 23: 7267-7273. 10.1038/sj.onc.1207946.CrossRefPubMed
20.
Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA, Kang J, Assanah M, McKhann GM, Sisti MB: Identification of A2B5+CD133- tumor-initiating cells in adult human gliomas. Neurosurgery. 2008, 62: 505-514. 10.1227/01.neu.0000316019.28421.95.CrossRefPubMed
21.
Mineo JF, Bordron A, Quintin-Roue I, Loisel S, Ster KL, Buhe V, Lagarde N, Berthou C: Recombinant humanised anti-HER2/neu antibody (Herceptin) induces cellular death of glioblastomas. Br J Cancer. 2004, 91: 1195-1199.PubMedPubMedCentral
22.
Kolenko V, Wang Q, Riedy MC, O’Shea J, Ritz J, Cathcart MK, Rayman P, Tubbs R, Edinger M, Novick A: Tumor-induced suppression of T lymphocyte proliferation coincides with inhibition of Jak3 expression and IL-2 receptor signaling: role of soluble products from human renal cell carcinomas. J Immunol. 1997, 159: 3057-3067.PubMed
23.
Yamauchi A, Taga K, Mostowski HS, Bloom ET: Target cell-induced apoptosis of interleukin-2-activated human natural killer cells: roles of cell surface molecules and intracellular events. Blood. 1996, 87: 5127-5135.PubMed
24.
Shiraki K, Tsuji N, Shioda T, Isselbacher KJ, Takahashi H: Expression of Fas ligand in liver metastases of human colonic adenocarcinomas. Proc Natl Acad Sci USA. 1997, 94: 6420-6425. 10.1073/pnas.94.12.6420.CrossRefPubMedPubMedCentral
25.
Saas P, Walker PR, Hahne M, Quiquerez AL, Schnuriger V, Perrin G, French L, Van Meir EG, de Tribolet N, Tschopp J, Dietrich PY: Fas ligand expression by astrocytoma in vivo: maintaining immune privilege in the brain?. J Clin Invest. 1997, 99: 1173-1178. 10.1172/JCI119273.CrossRefPubMedPubMedCentral
26.
O’Connell J, O’Sullivan GC, Collins JK, Shanahan F: The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med. 1996, 184: 1075-1082. 10.1084/jem.184.3.1075.CrossRefPubMed
27.
Niehans GA, Brunner T, Frizelle SP, Liston JC, Salerno CT, Knapp DJ, Green DR, Kratzke RA: Human lung carcinomas express Fas ligand. Cancer Res. 1997, 57: 1007-1012.PubMed
28.
Husain N, Chiocca EA, Rainov N, Louis DN, Zervas NT: Co-expression of Fas and Fas ligand in malignant glial tumors and cell lines. Acta Neuropathol. 1998, 95: 287-290. 10.1007/s004010050799.CrossRefPubMed
29.
Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D: Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science. 1996, 274: 1363-1366. 10.1126/science.274.5291.1363.CrossRefPubMed
30.
Nam KO, Shin SM, Lee HW: Cross-linking of 4-1BB up-regulates IL-13 expression in CD8(+) T lymphocytes. Cytokine. 2006, 33: 87-94. 10.1016/j.cyto.2005.12.003.CrossRefPubMed
31.
Kawakami M, Leland P, Kawakami K, Puri RK: Mutation and functional analysis of IL-13 receptors in human malignant glioma cells. Oncol Res. 2001, 12: 459-467.CrossRefPubMed
32.
Kapp U, Yeh WC, Patterson B, Elia AJ, Kagi D, Ho A, Hessel A, Tipsword M, Williams A, Mirtsos C: Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med. 1999, 189: 1939-1946. 10.1084/jem.189.12.1939.CrossRefPubMedPubMedCentral
33.
Oshima Y, Puri RK: Suppression of an IL-13 autocrine growth loop in a human Hodgkin/Reed-Sternberg tumor cell line by a novel IL-13 antagonist. Cell Immunol. 2001, 211: 37-42. 10.1006/cimm.2001.1828.CrossRefPubMed
34.
Ohshima K, Akaiwa M, Umeshita R, Suzumiya J, Izuhara K, Kikuchi M: Interleukin-13 and interleukin-13 receptor in Hodgkin’s disease: possible autocrine mechanism and involvement in fibrosis. Histopathology. 2001, 38: 368-375. 10.1046/j.1365-2559.2001.01083.x.CrossRefPubMed
35.
Skinnider BF, Elia AJ, Gascoyne RD, Trumper LH, von Bonin F, Kapp U, Patterson B, Snow BE, Mak TW: Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2001, 97: 250-255. 10.1182/blood.V97.1.250.CrossRefPubMed
36.
Formentini A, Prokopchuk O, Strater J, Kleeff J, Grochola LF, Leder G, Henne-Bruns D, Korc M, Kornmann M: Interleukin-13 exerts autocrine growth-promoting effects on human pancreatic cancer, and its expression correlates with a propensity for lymph node metastases. Int J Colorectal Dis. 2009, 24: 57-67. 10.1007/s00384-008-0550-9.CrossRefPubMed
37.
Heimberger AB, Sampson JH: Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma?. Neuro Oncol. 2011, 13: 3-13. 10.1093/neuonc/noq169.CrossRefPubMed
38.
Jacobs SK, Wilson DJ, Melin G, Parham CW, Holcomb B, Kornblith PL, Grimm EA: Interleukin-2 and lymphokine activated killer (LAK) cells in the treatment of malignant glioma: clinical and experimental studies. Neurol Res. 1986, 8: 81-87.PubMed
39.
Dillman RO, Duma CM, Schiltz PM, DePriest C, Ellis RA, Okamoto K, Beutel LD, De Leon C, Chico S: Intracavitary placement of autologous lymphokine-activated killer (LAK) cells after resection of recurrent glioblastoma. J Immunother. 2004, 27: 398-404. 10.1097/00002371-200409000-00009.CrossRefPubMed
40.
Hida T, Koike K, Sekido Y, Nishida K, Sugiura T, Ariyoshi Y, Takahashi T, Ueda R: Epitope analysis of cluster 1 and NK cell-related monoclonal antibodies. Br J Cancer Suppl. 1991, 14: 24-28.PubMedPubMedCentral
41.
Pfosser A, Brandl M, Salih H, Grosse-Hovest L, Jung G: Role of target antigen in bispecific-antibody-mediated killing of human glioblastoma cells: a pre-clinical study. Int J Cancer. 1999, 80: 612-616. 10.1002/(SICI)1097-0215(19990209)80:4<612::AID-IJC21>3.0.CO;2-K.CrossRefPubMed
42.
Jung G, Brandl M, Eisner W, Fraunberger P, Reifenberger G, Schlegel U, Wiestler OD, Reulen HJ, Wilmanns W: Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes: evidence for in situ t-cell activation and therapeutic efficacy. Int J Cancer. 2001, 91: 225-230. 10.1002/1097-0215(200002)9999:9999<::AID-IJC1038>3.3.CO;2-7.CrossRefPubMed
43.
Nishimura T, Nakamura Y, Takeuchi Y, Gao XH, Tokuda Y, Okumura K, Habu S: Bispecific antibody-directed antitumor activity of human CD4+ helper/killer T cells induced by anti-CD3 monoclonal antibody plus interleukin 2. Jpn J Cancer Res. 1991, 82: 1207-1210. 10.1111/j.1349-7006.1991.tb01782.x.CrossRefPubMed
44.
Nishimura T, Nakamura Y, Takeuchi Y, Tokuda Y, Iwasawa M, Kawasaki A, Okumura K, Habu S: Generation propagation, and targeting of human CD4+ helper/killer T cells induced by anti-CD3 monoclonal antibody plus recombinant IL-2. An efficient strategy for adoptive tumor immunotherapy. J Immunol. 1992, 148: 285-291.PubMed
45.
Hishii M, Nitta T, Ebato M, Okumura K, Sato K: Targeting therapy for glioma by LAK cells coupled with bispecific antibodies. J Clin Neurosci. 1994, 1: 261-265. 10.1016/0967-5868(94)90067-1.CrossRefPubMed
46.
Davico Bonino L, De Monte LB, Spagnoli GC, Vola R, Mariani M, Barone D, Moro AM, Riva P, Nicotra MR, Natali PG: Bispecific monoclonal antibody anti-CD3 x anti-tenascin: an immunotherapeutic agent for human glioma. Int J Cancer. 1995, 61: 509-515. 10.1002/ijc.2910610414.CrossRefPubMed
Metadata
Title
Targeting and killing of glioblastoma with activated T cells armed with bispecific antibodies
Authors
Ian M Zitron
Archana Thakur
Oxana Norkina
Geoffrey R Barger
Lawrence G Lum
Sandeep Mittal
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-83

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