Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma
| Autor: | Christine E. Brown, Uyen Tran, Eugenia Zah, Eunwoo Nam, Brenda Y. Ji, Xiuli Wang, Vinya Bhuvan, Yvonne Y. Chen, Stanley B. Gosliner |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytotoxicity Immunologic medicine.medical_treatment T-Lymphocytes Cytotoxicity Cell Adoptive Programmed Cell Death 1 Receptor General Physics and Astronomy Cancer immunotherapy Immunotherapy Adoptive Cell therapy 0302 clinical medicine Immunologic Receptors Medicine CD8-positive T cells lcsh:Science Multiple myeloma Cancer Gene Editing Multidisciplinary Receptors Chimeric Antigen biology Hematology medicine.anatomical_structure 5.1 Pharmaceuticals 030220 oncology & carcinogenesis Tumour immunology Immunotherapy Development of treatments and therapeutic interventions Antibody Multiple Myeloma Biotechnology Combination therapy Science General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Rare Diseases Antigen Clinical Research In vivo Antigens Neoplasm Humans Antigens B-Cell Maturation Antigen business.industry Chimeric Antigen General Chemistry medicine.disease Chimeric antigen receptor 030104 developmental biology Orphan Drug biology.protein Cancer research Neoplasm lcsh:Q business K562 Cells human activities Immunologic Memory |
| Zdroj: | Nature communications, vol 11, iss 1 Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-13 (2020) |
| Popis: | Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multiple myeloma (MM) that is resistant to conventional CAR-T cell therapy targeting B-cell maturation antigen (BCMA). We demonstrate that BCMA/CS1 bispecific CAR-T cells exhibit superior CAR expression and function compared to T cells that co-express individual BCMA and CS1 CARs. Combination therapy with anti–PD-1 antibody further accelerates the rate of initial tumor clearance in vivo, while CAR-T cell treatment alone achieves durable tumor-free survival even upon tumor re-challenge. Taken together, the BCMA/CS1 bispecific CAR presents a promising treatment approach to prevent antigen escape in CAR-T cell therapy against MM, and the vertically integrated optimization process can be used to develop robust cell-based therapy against novel disease targets. One cause of relapse in cancer patients treated with chimeric antigen receptor (CAR) T cells is the loss of CAR-targeted antigens, which is particularly common in multiple myeloma (MM). Here the authors engineer a CAR recognizing two common MM-associated antigens and demonstrate its superiority to single-antigen CARs in a mouse model of MM. |
| Databáze: | OpenAIRE |
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