Monoclonal antibody 3H11 chimeric antigen receptors enhance T cell effector function and exhibit efficacy against gastric cancer

Han,Haibo; Wang,Shanshan; Hu,Ying; Li,Zhaowei; Yang,Wei; Lv,Yunwei; Wang,Limin; Zhang,Lianhai; Ji,Jiafu

doi:10.3892/ol.2018.8255

Monoclonal antibody 3H11 chimeric antigen receptors enhance T cell effector function and exhibit efficacy against gastric cancer

Authors:
- Haibo Han
- Shanshan Wang
- Ying Hu
- Zhaowei Li
- Wei Yang
- Yunwei Lv
- Limin Wang
- Lianhai Zhang
- Jiafu Ji
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Affiliations: Department of Biobank, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, Department of Clinical Laboratory, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
Published online on: March 13, 2018 https://doi.org/10.3892/ol.2018.8255
Pages: 6887-6894
Copyright: © Han et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although chimeric antigen receptor T cell (CAR‑T) therapies for certain types of solid tumors have been used in clinical trials, novel CARs that are able to target gastric cancer (GC) are still required. In our previous study, monoclonal antibody 3H11 (mAb 3H11), generated from immunization with five human GC cell lines, was demonstrated to have a 93.5% positive reaction with a clear membrane location and more than 5% cancer cell staining in GC tissues in our previous study. In the present study, 3H11‑CARs were designed for modified T cell therapy. To begin with, it was confirmed that the single‑chain variable fragment (scFV) of the mAb 3H11, known as scFV‑3H11, exhibited similar activity with the natural antibody. In addition, scFV‑3H11 CAR‑T cells are able to kill tumor cells accompanied with increased interleukin‑2 and interferon‑γ secretion in vitro, and reduced the tumor burden in GC cell lines and patient‑derived GC cells in vivo. In conclusion, scFV‑3H11 CARs may have the potential to treat mAb 3H11‑positive GC.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Zong L, Abe M, Seto Y and Ji J: The challenge of screening for early gastric cancer in China. Lancet. 388:26062016. View Article : Google Scholar : PubMed/NCBI
4	Johnson LA and June CH: Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 27:38–58. 2017. View Article : Google Scholar : PubMed/NCBI
5	Essand M and Loskog AS: Genetically engineered T cells for the treatment of cancer. J Intern Med. 273:166–181. 2013. View Article : Google Scholar : PubMed/NCBI
6	Batlevi CL, Matsuki E, Brentjens RJ and Younes A: Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol. 13:25–40. 2016. View Article : Google Scholar : PubMed/NCBI
7	Wei SM: Monoclonal antibodies against gastric cancer and their selective reaction on various tissues. Zhonghua Zhong Liu Za Zhi. 11:162–164. 1989.(In Chinese). PubMed/NCBI
8	Xu G, Zhang M, Liu B, Li Z, Lin B, Xu X, Jin M, Li J, Wu J, Dong Z, et al: Radioimmunoguided surgery in gastric cancer using 131-I labeled monoclonal antibody 3H11. Semin Surg Oncol. 10:88–94. 1994. View Article : Google Scholar : PubMed/NCBI
9	Wang C, Wang Y, Su X, Lin B, Xu X, Zhang M, Li J and Xu G: Iodine-125 labeled monoclonal antibody 3H11: In radioimmunoguided surgery for primary gastric cancer. Zhonghua Wai Ke Za Zhi. 38:507–509. 2000.(In Chinese). PubMed/NCBI
10	Li J, Wang Y, Li QX, Wang YM, Xu JJ and Dong ZW: Cloning of 3H11 mAb variable region gene and expression of 3H11 human-mouse chimeric light Chain. World J Gastroenterol. 4:41–44. 1998. View Article : Google Scholar : PubMed/NCBI
11	Chen D and Shou C: Molecular cloning of a tumor-associated antigen recognized by monoclonal antibody 3H11. Biochem Biophys Res Commun. 280:99–103. 2001. View Article : Google Scholar : PubMed/NCBI
12	Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B, Timofeeva OA, Nealon C, Dakic A, Simic V, et al: ROCK inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol. 180:599–607. 2012. View Article : Google Scholar : PubMed/NCBI
13	Ye J, Ma N, Madden TL and Ostell JM: IgBLAST: An immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res. 41:(Web Server Issue). W34–W40. 2013. View Article : Google Scholar : PubMed/NCBI
14	Enblad G, Karlsson H and Loskog AS: CAR T-Cell therapy: The role of physical barriers and immunosuppression in lymphoma. Hum Gene Ther. 26:498–505. 2015. View Article : Google Scholar : PubMed/NCBI
15	Tang XY, Sun Y, Zhang A, Hu GL, Cao W, Wang DH, Zhang B and Chen H: Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: A non-randomised, open-label phase I trial protocol. BMJ Open. 6:e0139042016. View Article : Google Scholar : PubMed/NCBI
16	Ozawa K: Current status and future development of CAR-T gene therapy. Rinsho Ketsueki. 56:2180–2185. 2015.(In Japanese). PubMed/NCBI
17	Davenport AJ, Jenkins MR, Ritchie DS, Prince HM, Trapani JA, Kershaw MH, Darcy PK and Neeson PJ: CAR-T cells are serial killers. Oncoimmunology. 4:e10536842015. View Article : Google Scholar : PubMed/NCBI
18	Schneider U, Schwenk HU and Bornkamm G: Characterization of EBV-genome negative ‘null’ and ‘T’ cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non-Hodgkin lymphoma. Int J Cancer. 19:621–626. 1977. View Article : Google Scholar : PubMed/NCBI
19	Kobayashi E, Kishi H, Ozawa T, Hamana H, Nakagawa H, Jin A, Lin Z and Muraguchi A: A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells. Biochem Biophys Res Commun. 453:798–803. 2014. View Article : Google Scholar : PubMed/NCBI
20	Shirasu N, Shibaguci H and Kuroki M, Yamada H and Kuroki M: Construction and molecular characterization of human chimeric T-cell antigen receptors specific for carcinoembryonic antigen. Anticancer Res. 30:2731–2738. 2010.PubMed/NCBI
21	Jamnani FR, Rahbarizadeh F, Shokrgozar MA, Mahboudi F, Ahmadvand D, Sharifzadeh Z, Parhamifar L and Moghimi SM: T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: Towards tumor-directed oligoclonal T cell therapy. Biochim Biophys Acta. 1840:378–386. 2014. View Article : Google Scholar : PubMed/NCBI
22	Khaleghi S, Rahbarizadeh F, Ahmadvand D, Rasaee MJ and Pognonec P: A caspase 8-based suicide switch induces apoptosis in nanobody-directed chimeric receptor expressing T cells. Int J Hematol. 95:434–444. 2012. View Article : Google Scholar : PubMed/NCBI
23	Zhang Q, Wang H, Li H, Xu J, Tian K, Yang J, Lu Z and Zheng J: Chimeric antigen receptor-modified T Cells inhibit the growth and metastases of established tissue factor-positive tumors in NOG mice. Oncotarget. 8:9488–9499. 2017.PubMed/NCBI
24	Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, Huls MH, Liu E, Gee AP, Mei Z, et al: Virus-specific T cells engineered to coexpress tumor-specific receptors: Persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 14:1264–1270. 2008. View Article : Google Scholar : PubMed/NCBI
25	Zuccolotto G, Fracasso G, Merlo A, Montagner IM, Rondina M, Bobisse S, Figini M, Cingarlini S, Colombatti M, Zanovello P and Rosato A: PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models. PLoS One. 9:e1094272014. View Article : Google Scholar : PubMed/NCBI
26	Craddock JA, Lu A, Bear A, Pule M, Brenner MK, Rooney CM and Foster AE: Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J Immunother. 33:780–788. 2010. View Article : Google Scholar : PubMed/NCBI
27	Caruana I, Savoldo B, Hoyos V, Weber G, Liu H, Kim ES, Ittmann MM, Marchetti D and Dotti G: Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat Med. 21:524–529. 2015. View Article : Google Scholar : PubMed/NCBI