Fully human CD19-specific chimeric antigen receptors for T-cell therapy
| العنوان: | Fully human CD19-specific chimeric antigen receptors for T-cell therapy |
|---|---|
| المؤلفون: | Yan Chen, Daniel Sommermeyer, Stanley R. Riddell, Steven M Shamah, Alexander I. Salter, Tyler Hill, Kendall M. Mohler |
| المصدر: | Leukemia |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Recombinant Fusion Proteins, T-Lymphocytes, medicine.medical_treatment, T cell, Antigens, CD19, chemical and pharmacologic phenomena, Mice, SCID, Immunotherapy, Adoptive, Article, CD19, Mice, 03 medical and health sciences, Transduction (genetics), 0302 clinical medicine, Immune system, Species Specificity, Antigen, Mice, Inbred NOD, Transduction, Genetic, Cell Line, Tumor, medicine, Animals, Humans, Gene Library, Mice, Knockout, biology, business.industry, Immunogenicity, Hematology, Immunotherapy, Burkitt Lymphoma, Xenograft Model Antitumor Assays, Chimeric antigen receptor, 3. Good health, HEK293 Cells, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Immunology, Cancer research, biology.protein, Female, K562 Cells, business, human activities, Single-Chain Antibodies |
| الوصف: | Impressive results have been achieved by adoptively transferring T-cells expressing CD19-specific CARs with binding domains from murine mAbs to treat B-cell malignancies. T-cell mediated immune responses specific for peptides from the murine scFv antigen-binding domain of the CAR can develop in patients and result in premature elimination of CAR T-cells increasing the risk of tumor relapse. As fully human scFv might reduce immunogenicity, we generated CD19-specific human scFvs with similar binding characteristics as the murine FMC63-derived scFv using human Ab/DNA libraries. CARs were constructed in various formats from several scFvs and used to transduce primary human T-cells. The resulting CD19-CAR T-cells were specifically activated by CD19-positive tumor cell lines and primary chronic lymphocytic leukemia cells, and eliminated human lymphoma xenografts in immunodeficient mice. Certain fully human CAR constructs were superior to the FMC63-CAR, which is widely used in clinical trials. Imaging of cell surface distribution of the human CARs revealed no evidence of clustering without target cell engagement, and tonic signaling was not observed. To further reduce potential immunogenicity of the CARs, we also modified the fusion sites between different CAR components. The described fully human CARs for a validated clinical target may reduce immune rejection compared with murine-based CARs. |
| تدمد: | 1476-5551 0887-6924 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::01bd3743462f531530bee1df34c320b2Test https://doi.org/10.1038/leu.2017.57Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....01bd3743462f531530bee1df34c320b2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765551 08876924 |
|---|