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Circular mRNA-based TCR-T offers a safe and effective therapeutic strategy for treatment of cytomegalovirus infection
- Source :
- Molecular Therapy; 20230101, Issue: Preprints
- Publication Year :
- 2023
-
Abstract
- Circular mRNA (cmRNA) is particular useful due to its high resistant to degradation by exonucleases, resulting in greater stability and protein expression compared to linear mRNA. T cell receptor (TCR)-engineered T cells (TCR-T) represent a promising means of treating viral infections and cancer. This study aimed to evaluate the feasibility and efficacy of cmRNA in antigen-specific-TCR discovery and TCR-T therapy. Using human cytomegalovirus (CMV) pp65 antigen as a model, we found that the expansion of pp65-responsive-T cells was induced more effectively by monocyte-derived dendritic cells (moDCs) transfected with pp65-encoding cmRNA compared to linear mRNA. Subsequently, we developed cmRNA-transduced pp65-TCR-T (cm-pp65-TCR-T) that specifically targets the CMV-pp65 epitope. Our results showed that pp65-TCR could be expressed on primary T cells for more than 7 days. Moreover, both in vitrokilling and in vivoCDX models demonstrated that cm-pp65-TCR-T cells specifically and persistently kill pp65- and HLA-expressing tumor cells, significantly prolonging the survival of mice. Collectively, our results demonstrated that circular mRNA can be used as a more effective technical approach for antigen-specific TCR isolation and identification, and cm-pp65-TCR-T may provide a safe, non-viral, non-integrated therapeutic approach for controlling CMV infection, particularly in patients who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Details
- Language :
- English
- ISSN :
- 15250016 and 15250024
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Molecular Therapy
- Publication Type :
- Periodical
- Accession number :
- ejs64543058
- Full Text :
- https://doi.org/10.1016/j.ymthe.2023.11.017