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| Item Type: | Article |
|---|---|
| Title: | Engineering AvidCARs for combinatorial antigen recognition and reversible control of CAR function |
| Creators: |
Salzer, B.  ORCID: https://orcid.org/0000-0003-4282-6356, Schueller, C.M. ORCID: https://orcid.org/0000-0001-7618-6815, Zajc, C.U. ORCID: https://orcid.org/0000-0002-9356-7430, Peters, T., Schoeber, M.A. ORCID: https://orcid.org/0000-0003-4918-5061, Kovacic, B. ORCID: https://orcid.org/0000-0001-7261-0201, Buri, M.C., Lobner, E. ORCID: https://orcid.org/0000-0002-5234-5524, Dushek, O. ORCID: https://orcid.org/0000-0001-5847-5226, Huppa, J.B. ORCID: https://orcid.org/0000-0003-2634-8198, Obinger, C. ORCID: https://orcid.org/0000-0002-7133-3430, Putz, E.M. ORCID: https://orcid.org/0000-0002-9990-4477, Holter, W., Traxlmayr, M.W. ORCID: https://orcid.org/0000-0002-2108-582X and Lehner, M. ORCID: https://orcid.org/0000-0002-5776-4218
|
| Abstract: | T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity. |
| Keywords: | Neoplasm Antigens, B-Lymphocytes, Cultured Cells, Cytokines, Immunologic Cytotoxicity, Adoptive Immunotherapy, Lymphocyte Activation, Inbred NOD Mice, Knockout Mice, SCID Mice, Neoplasms, T-Cell Antigen Receptors, Chimeric Antigen Receptors, T-Lymphocytes, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 11 |
| Number: | 1 |
| Page Range: | 4166 |
| Date: | 20 August 2020 |
| Official Publication: | https://doi.org/10.1038/s41467-020-17970-3 |
| PubMed: | View item in PubMed |
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