T-cell receptor gene therapy targeting melanoma-associated antigen-A4 inhibits human tumor growth in non-obese diabetic/SCID/γcnull mice
| Autor: | Hiroshi Shiku, Yukari Mizuno, Junichi Mineno, Linan Wang, Eiichi Sato, Naoko Imai, Kazutoh Takesako, Chisaki Amaike, Hiroaki Ikeda, Mamoru Ito, Ikuei Nukaya, Yoshitaka Shirakura |
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| Rok vydání: | 2011 |
| Předmět: |
Cytotoxicity
Immunologic endocrine system Cancer Research Lung Neoplasms Esophageal Neoplasms Receptors Antigen T-Cell alpha-beta medicine.medical_treatment Genetic enhancement T cell Genetic Vectors Mice SCID CD8-Positive T-Lymphocytes Biology Immunotherapy Adoptive Immunoenzyme Techniques Cell therapy Mice Cancer immunotherapy Antigen Antigens Neoplasm Mice Inbred NOD Transduction Genetic medicine Animals Humans Melanoma-associated antigen HLA-A Antigens T-cell receptor Genetic Therapy General Medicine Immunotherapy Flow Cytometry Combined Modality Therapy Neoplasm Proteins Retroviridae medicine.anatomical_structure Oncology Vaccines Subunit Immunology Leukocytes Mononuclear Female |
| Zdroj: | Cancer Science. 103:17-25 |
| ISSN: | 1347-9032 |
| DOI: | 10.1111/j.1349-7006.2011.02111.x |
| Popis: | Adoptive cell therapy with lymphocytes that have been genetically engineered to express tumor-reactive T-cell receptors (TCR) is a promising approach for cancer immunotherapy. We have been exploring the development of TCR gene therapy targeting cancer/testis antigens, including melanoma-associated antigen (MAGE) family antigens, that are ideal targets for adoptive T-cell therapy. The efficacy of TCR gene therapy targeting MAGE family antigens, however, has not yet been evaluated in vivo. Here, we demonstrate the in vivo antitumor activity in immunodeficient non-obese diabetic/SCID/γc(null) (NOG) mice of human lymphocytes genetically engineered to express TCR specific for the MAGE-A4 antigen. Polyclonal T cells derived from human peripheral blood mononuclear cells were transduced with the αβ TCR genes specific for MAGE-A4, then adoptively transferred into NOG mice inoculated with MAGE-A4 expressing human tumor cell lines. The transferred T cells maintained their effector function in vivo, infiltrated into tumors, and inhibited tumor growth in an antigen-specific manner. The combination of adoptive cell therapy with antigen peptide vaccination enhanced antitumor activity, with improved multifunctionality of the transferred cells. These data suggest that TCR gene therapy with MAGE-A4-specific TCR is a promising strategy to treat patients with MAGE-A4-expressing tumors; in addition, the acquisition of multifunctionality in vivo is an important factor to predict the quality of the T-cell response during adoptive therapy with human lymphocytes. |
| Databáze: | OpenAIRE |
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