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| Item Type: | Article |
|---|---|
| Title: | EBAG9-silencing exerts an immune checkpoint function without aggravating adverse effects |
| Creators Name: | Wirges, A. and Bunse, M. and Joedicke, J.J. and Blanc, E. and Gudipati, V. and Moles, M.W. and Shiku, H. and Beule, D. and Huppa, J.B. and Höpken, U.E. and Rehm, A. |
| Abstract: | Chimeric antigen receptor (CAR) T cells have revolutionized treatment of B-cell malignancies. However, enhancing the efficacy of engineered T cells without compromising their safety is warranted. The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) inhibits release of cytolytic enzymes from cytotoxic T lymphocytes. Here, we examined the potency of EBAG9-silencing for the improvement of adoptive T cell therapy. Micro-RNA-mediated EBAG9 downregulation in transplanted CTLs from immunized mice improved their cytolytic competence in a tumor model. In tolerant female recipient mice that received organ transplants, a minor histocompatibility antigen was turned into a rejection antigen by Ebag9 deletion, indicating an immune checkpoint function for EBAG9. Considerably less EBAG9-silenced human CAR T cells were needed for tumor growth control in a xenotransplantation model. Transcriptome profiling did not reveal additional risks regarding genotoxicity or aberrant differentiation. A single-step retrovirus transduction process links CAR or TCR expression with miRNA-mediated EBAG9 downregulation. Despite higher cytolytic efficacy, release of cytokines associated with cytokine release syndrome remains unaffected. Collectively, EBAG9-silencing enhances effector capacity of TCR- and CAR-engineered T cells, results in improved tumor eradication, facilitates efficient manufacturing, and decreases the therapeutic dose. |
| Keywords: | Cancer Immunotherapy, Chimeric Antigen Receptor T Cells, Secretory Pathway, Cytolytic Capacity, Hematologic Malignancies, Adoptive T Cell Therapy, Multiple Myeloma, Leukemia, Animals, Mice |
| Source: | Molecular Therapy |
| ISSN: | 1525-0016 |
| Publisher: | Cell Press / Elsevier |
| Volume: | 30 |
| Number: | 11 |
| Page Range: | 3358-3378 |
| Date: | 2 November 2022 |
| Official Publication: | https://doi.org/10.1016/j.ymthe.2022.07.009 |
| PubMed: | View item in PubMed |
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