CD3 aptamers promote expansion and persistence of tumor-reactive T cells for adoptive T cell therapy in cancer

Menon, A.P.; Villanueva, H.; Meraviglia-Crivelli, D.; van Santen, H.M.; Hellmeier, J.; Zheleva, A.; Nonateli, F.; Peters, T.; Wachsmann, T.L.A.; Hernandez-Rueda, M.; Huppa, J.B.; Schütz, G.J.; Sevcsik, E.; Moreno, B.; Pastor, F.

CD3 aptamers promote expansion and persistence of tumor-reactive T cells for adoptive T cell therapy in cancer

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Item Type:	Article
Title:	CD3 aptamers promote expansion and persistence of tumor-reactive T cells for adoptive T cell therapy in cancer
Creators Name:	Menon, A.P., Villanueva, H., Meraviglia-Crivelli, D., van Santen, H.M., Hellmeier, J., Zheleva, A., Nonateli, F., Peters, T., Wachsmann, T.L.A., Hernandez-Rueda, M., Huppa, J.B., Schütz, G.J., Sevcsik, E., Moreno, B. and Pastor, F.
Abstract:	The CD3/T cell receptor (TCR) complex is responsible for antigen-specific pathogen recognition by T cells, and initiates the signaling cascade necessary for activation of effector functions. CD3 agonistic antibodies are commonly used to expand T lymphocytes in a wide range of clinical applications, including in adoptive T cell therapy for cancer patients. A major drawback of expanding T cell populations ex vivo using CD3 agonistic antibodies is that they expand and activate T cells independent of their TCR antigen specificity. Therapeutic agents that facilitate expansion of T cells in an antigen-specific manner and reduce their threshold of T cell activation are therefore of great interest for adoptive T cell therapy protocols. To identify CD3-specific T cell agonists, several RNA aptamers were selected against CD3 using Systematic Evolution of Ligands by EXponential enrichment combined with high-throughput sequencing. The extent and specificity of aptamer binding to target CD3 were assessed through surface plasma resonance, P32 double-filter assays, and flow cytometry. Aptamer-mediated modulation of the threshold of T cell activation was observed in vitro and in preclinical transgenic TCR mouse models. The aptamers improved efficacy and persistence of adoptive T cell therapy by low-affinity TCR-reactive T lymphocytes in melanoma-bearing mice. Thus, CD3-specific aptamers can be applied as therapeutic agents which facilitate the expansion of tumor-reactive T lymphocytes while conserving their tumor specificity. Furthermore, selected CD3 aptamers also exhibit cross-reactivity to human CD3, expanding their potential for clinical translation and application in the future.
Keywords:	MT: Oligonucleotides: Therapies and Applications, CD3, Aptamer, Cancer Immunotherapy, Adoptive T Cell Therapy
Source:	Molecular Therapy Nucleic Acids
ISSN:	2162-2531
Publisher:	Cell Press / Elsevier
Volume:	35
Number:	2
Page Range:	102198
Date:	11 June 2024
Official Publication:	https://doi.org/10.1016/j.omtn.2024.102198
PubMed:	View item in PubMed

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