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Background: Anti-CD19 chimeric antigen receptor T cell therapies (CAR-T) have shown impressive clinical outcomes in relapsed/refractory (R/R) CD19+ B-cell non-Hodgkin lymphomas (B-NHL) and acute lymphoblastic leukemias (B-ALL). However, 30%-60% of patients with B-ALL who initially responded to anti-CD19 CAR-T therapies relapsed either due to poor CAR-T persistence or CD19 antigen escape, and preliminary data also indicated CD19 antigen loss in patients with B-NHL relapsed after anti-CD19 CAR-T therapy. In addition, the immunogenicity of murine origin CAR construct is another cause of limited in vivo CAR-T persistence. Design: To overcome these problems, a novel fully human anti-CD19×anti-CD22 dual targeted CAR-T cell product - CT120, has been developed. The CT120 CAR molecule contains tandem fusion of anti-CD19 and anti-CD22 scFv, which can effectively recognize CD19 and CD22 antigen independently, to avoid antigen escape. The intracellular CAR domain contains CD3ζ and 4-1BB co-stimulatory domain, which can improve in vivo persistence. In addition, both anti-CD19 and anti-CD22 antibody were generated from proprietary fully human libraries to minimize possible immunogenicity. The CAR molecule was transferred to autologous T cells through a lentiviral backbone. Results: The anti-CD19 and anti-CD22 scFv binds to its antigen in nanomolar range, and CT120 CAR-T cells can bind to both CD19 and CD22 antigens in a noncompetitive manner. CT120 CAR-T cells showed potent in vitro cytotoxicity not only to target B-cell lymphoma/leukemia cell lines (Raji, Daudi, and NALM-6), but also to the CD19 knockout (CD19-CD22+) and CD22 knockout (CD19+CD22-) Raji cell lines. CT120 can secret multiple cytokines, such as IL-2, TNF-α and IFN-γ, and proliferate efficiently after engagement of target cells. In vivo efficacy study demonstrated that CT120 CAR-T cells expanded effectively in mice and completely inhibit Raji and NALM-6 tumor cell growth. Furthermore, CT120 showed a favorable safety profile and promising efficacy in patients with r/r B-NHL and B-ALL in an investigator-initiated trial (IIT). Certain patients who relapsed after previous murine origin CAR-T treatment also benefited from CT120 therapy. Conclusion: Collectively, CT120 is a potent and safe anti-CD19×anti-CD22 dual target CAR-T product for the treatment of B-NHL and B-ALL, and now it is in registered phase 1/2 clinical trial. Citation Format: Panpan Niu, Qianli Hu, Jialu Mo, Guangrong Meng, Xiangyin Jia, Wei Cheng, Qiaoe Wei, Zhenyu Dai, Xuefeng Wu, Guang Hu, Taochao Tan, Jianfeng Zhou, Yongkun Yang, gang Hu. CT120, a novel fully human anti-CD19 x anti-CD22 dual targeted chimeric antigen receptor T cell product for the treatment of B-NHL and B-ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2811.

MiRNAs are a family of small non-coding RNAs that control levels of multiple proteins by post-transcriptionally decreasing messenger RNA stability and translation. MiRNA is a part of the epigenetic machinery. In addition to post-transcriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of epilepsy. However, miRNA not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenetic and MiRNA, and any dysregulation of this complex system can result in various physiological and pathological conditions. Currently, there is an unmet need for antiepileptic drugs that truly prevent the development of epilepsy in high-risk populations. New findings in animal models and human brain tissue suggest that microRNAs play a crucial role in epileptogenesis and the pathophysiology of chronic epilepsy. Objectives: This paper focuses on the epigenetic role of miRNA in the development of epilepsy and potential targets for drug therapy. Methods: In this paper, through the keywords epilepsy, epigenetic, methylation, miRNA, non-coding RNA search in PubMed, SPIS, GeenMedical, Google Scholar and Web of Science, to study the potential application of miRNA epigenetic regulation in the treatment of epilepsy. Results: Future treatments that manipulate miRNA epigenetic processes, such as Anti-oligonucleotides, DNA methylation and Nucleic Acid Aptamers, to treat or prevent epilepsy. Conclusion: Overall, miRNA epigenetic drugs have become a new frontier target to achieve a cure for epilepsy.