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

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.

[1]  Jie Yang,et al.  Chimeric antigen receptor-modified T Cells inhibit the growth and metastases of established tissue factor-positive tumors in NOG mice , 2016, Oncotarget.

[2]  C. June,et al.  Driving gene-engineered T cell immunotherapy of cancer , 2016, Cell Research.

[3]  A. Zhang,et al.  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 , 2016, BMJ Open.

[4]  J. Ji,et al.  The challenge of screening for early gastric cancer in China , 2016, The Lancet.

[5]  A. Jemal,et al.  Cancer statistics in China, 2015 , 2016, CA: a cancer journal for clinicians.

[6]  K. Ozawa.  [Current status and future development of CAR-T gene therapy]. , 2015, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[7]  G. Enblad,et al.  CAR T-Cell Therapy: The Role of Physical Barriers and Immunosuppression in Lymphoma. , 2015, Human gene therapy.

[8]  J. Trapani,et al.  CAR-T cells are serial killers , 2015, Oncoimmunology.

[9]  Eugene S. Kim,et al.  Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T-lymphocytes , 2015, Nature Medicine.

[10]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[11]  H. Hamana,et al.  A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells. , 2014, Biochemical and biophysical research communications.

[12]  A. Rosato,et al.  PSMA-Specific CAR-Engineered T Cells Eradicate Disseminated Prostate Cancer in Preclinical Models , 2014, PloS one.

[13]  Ning Ma,et al.  IgBLAST: an immunoglobulin variable domain sequence analysis tool , 2013, Nucleic Acids Res..

[14]  M. Essand,et al.  Genetically engineered T cells for the treatment of cancer , 2013, Journal of internal medicine.

[15]  D. Ahmadvand,et al.  A caspase 8-based suicide switch induces apoptosis in nanobody-directed chimeric receptor expressing T cells , 2012, International Journal of Hematology.

[16]  C. Rooney,et al.  Enhanced Tumor Trafficking of GD2 Chimeric Antigen Receptor T Cells by Expression of the Chemokine Receptor CCR2b , 2010, Journal of immunotherapy.

[17]  M. Kuroki,et al.  Construction and molecular characterization of human chimeric T-cell antigen receptors specific for carcinoembryonic antigen. , 2010, Anticancer research.

[18]  Hao Liu,et al.  Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma , 2008, Nature Medicine.

[19]  H. Ma,et al.  [Molecular cloning of the tumor associated antigen recognized by monoclonal antibody 3H11]. , 2001, Zhonghua yi xue za zhi.

[20]  X. Su,et al.  [Iodine-125 labeled monoclonal antibody 3H11: in radioimmunoguided surgery for primary gastric cancer]. , 2000, Zhonghua wai ke za zhi [Chinese journal of surgery].

[21]  Yan Wang,et al.  Cloning of 3H11 mAb variable region gene and expression of 3H11 human-mouse chimeric light Chain. , 1998, World journal of gastroenterology.

[22]  J. Li,et al.  Radioimmunoguided surgery in gastric cancer using 131-I labeled monoclonal antibody 3H11. , 1994, Seminars in surgical oncology.

[23]  Weissman Sm.  Monoclonal antibodies against gastric cancer and their selective reaction on various tissues , 1989 .

[24]  G. Bornkamm,et al.  Characterization of EBV‐genome negative “null” and “T” cell lines derived from children with acute lymphoblastic leukemia and leukemic transformed non‐Hodgkin lymphoma , 1977, International journal of cancer.

[25]  A. Younes,et al.  Novel immunotherapies in lymphoid malignancies , 2016, Nature Reviews Clinical Oncology.

[26]  M. Shokrgozar,et al.  T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: towards tumor-directed oligoclonal T cell therapy. , 2014, Biochimica et biophysica acta.

[27]  J. Rhim,et al.  Epithelial and Mesenchymal Cell Biology ROCK Inhibitor and Feeder Cells Induce the Conditional Reprogramming of Epithelial Cells , 2012 .

[28]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[29]  C. Shou,et al.  Molecular cloning of a tumor-associated antigen recognized by monoclonal antibody 3H11. , 2001, Biochemical and biophysical research communications.

[30]  S. M. Wei.  [Monoclonal antibodies against gastric cancer and their selective reaction on various tissues]. , 1989, Zhonghua zhong liu za zhi [Chinese journal of oncology].