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EBAG9-silencing exerts an immune checkpoint function without aggravating adverse effects

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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
Publisher:Cell Press / Elsevier
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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