Versatile strategy for controlling the specificity and activity of engineered T cells
| Autor: | Travis S. Young, Sophie B. Sun, Holly Pugh, Hwayoung Yun, Timothy M. Wright, Stephanie A. Kazane, Chan Hyuk Kim, Ji Young Kim, James N. Kochenderfer, Peter G. Schultz, Bryan R. Fonslow, Jennifer S. Y. Ma, Min Soo Kim, Sei-hyun Choi, Oded Singer, David T. Rodgers, Yu Cao |
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| Rok vydání: | 2016 |
| Předmět: |
Cytotoxicity
Immunologic Models Molecular 0301 basic medicine Adoptive cell transfer Protein Conformation Sialic Acid Binding Ig-like Lectin 2 T-Lymphocytes medicine.medical_treatment Cell T-Cell Antigen Receptor Specificity Mice SCID Lymphocyte Activation Protein Engineering Immunotherapy Adoptive Immunological synapse Mice Cancer immunotherapy Mice Inbred NOD Transduction Genetic B-Lymphocytes Multidisciplinary Cell biology medicine.anatomical_structure PNAS Plus Female Fluorescein-5-isothiocyanate Azides Phenylalanine Recombinant Fusion Proteins Antigens CD19 Genetic Vectors Receptors Antigen T-Cell Biology CD19 03 medical and health sciences Antigens Neoplasm In vivo Cell Line Tumor Lymphopenia Leukemia B-Cell medicine Animals Humans Lentivirus Xenograft Model Antitumor Assays Molecular biology Chimeric antigen receptor Mice Inbred C57BL 030104 developmental biology Cancer cell biology.protein Single-Chain Antibodies |
| Zdroj: | Proceedings of the National Academy of Sciences. 113 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1524193113 |
| Popis: | The adoptive transfer of autologous T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a promising cancer therapy. Despite impressive clinical efficacy, the general application of current CAR-T--cell therapy is limited by serious treatment-related toxicities. One approach to improve the safety of CAR-T cells involves making their activation and proliferation dependent upon adaptor molecules that mediate formation of the immunological synapse between the target cancer cell and T-cell. Here, we describe the design and synthesis of structurally defined semisynthetic adaptors we refer to as "switch" molecules, in which anti-CD19 and anti-CD22 antibody fragments are site-specifically modified with FITC using genetically encoded noncanonical amino acids. This approach allows the precise control over the geometry and stoichiometry of complex formation between CD19- or CD22-expressing cancer cells and a "universal" anti-FITC-directed CAR-T cell. Optimization of this CAR-switch combination results in potent, dose-dependent in vivo antitumor activity in xenograft models. The advantage of being able to titrate CAR-T-cell in vivo activity was further evidenced by reduced in vivo toxicity and the elimination of persistent B-cell aplasia in immune-competent mice. The ability to control CAR-T cell and cancer cell interactions using intermediate switch molecules may expand the scope of engineered T-cell therapy to solid tumors, as well as indications beyond cancer therapy. |
| Databáze: | OpenAIRE |
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