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

Wirges, A.; Bunse, M.; Joedicke, J.J.; Blanc, E.; Gudipati, V.; Moles, M.W.; Shiku, H.; Beule, D.; Huppa, J.B.; Höpken, U.E.; Rehm, A.

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., Bunse, M., Joedicke, J.J., Blanc, E., Gudipati, V., Moles, M.W., Shiku, H., Beule, D., Huppa, J.B., 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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