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RNAi effectors (e.g. siRNA, shRNA and miRNA) can trigger the silencing of specific genes causing alteration of genomic functions becoming a new therapeutic area for the treatment of infectious diseases, neurodegenerative disorders and cancer. In cancer treatment, RNAi effectors showed potential immunomodulatory actions by down-regulating immuno-suppressive proteins, such as PD-1 and CTLA-4, which restrict immune cell function and present challenges in cancer immunotherapy. Therefore, compared with extracellular targeting by antibodies, RNAi-mediated cell-intrinsic disruption of inhibitory pathways in immune cells could promote an increased anti-tumour immune response. Along with non-viral vectors, DNA-based RNAi strategies might be a more promising method for immunomodulation to silence multiple inhibitory pathways in T cells than immune checkpoint blockade antibodies. Thus, in this review, we discuss diverse RNAi implementation strategies, with recent viral and non-viral mediated RNAi synergism to immunotherapy that augments the anti-tumour immunity. Finally, we provide the current progress of RNAi in clinical pipeline. [ABSTRACT FROM AUTHOR]

High interleukin 17A (IL-17A) expression in hepatocellular carcinoma (HCC) tissue promotes HCC development. This study explores a method to inhibit HCC growth by neutralizing IL-17A in the HCC microenvironment. A novel type 5 adenoviral vector (Ad5) that carries DNA sequences encoding specific neutralizing IL-17A recombinant antibody fragments was developed in this research. After locally injecting into tumor tissues, the Ad5 transduced into tumor cells. This leads to the expression of the anti-IL-17A recombinant antibody fragments in the HCC tissue and consequently to an inhibition of HCC growth by neutralizing IL-17A. The stability of the antibody fragments was optimized by different structures design. Stable HCC cell lines that secrete IL-17A continuously were constructed, which showed stronger invasion and migration ability than control HCC cell lines. In addition, the enhanced migration and invasion ability were partially reversed by applying the adenoviral vectors. These results suggest that IL-17A might promote HCC growth by enhancing the invasion and migration ability of hepatoma cells. The antibody fragments from Ad5 neutralized IL-17A locally, in turn inhibiting the growth of HCC tumors. In conclusion, the local administration of Ad5 vectors encoding IL-17A-neutralizing antibody fragments provides a new option for HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Persistence of CAR-T cell function is associated with relapse rate after CAR-T therapy, while co-stimulatory agents are highly concerned with the persistence of CAR-T cells. In this study, we designed and constructed a series of BCMA-targeting second-generation CAR constructs containing CD28, 41BB, and OX40 molecules, respectively, to identify the costimulatory domains most favorable for persistence. The results of routine in vitro studies showed that OX40-CAR-T and 41BB-CAR-T had similar antitumor effects and were superior to CD28-CAR-T in terms of proliferation and cytotoxicity. Although difficult to distinguish by conventional functional assays, OX40-CAR-T cells exhibited greater proliferation and enhanced immune memory than 41BB-CAR-T cells with the repeated stimulation assay by BCMA-expressing target cells. In vivo studies further demonstrated that OX40-CAR-T cells had stronger proliferative activity than 41BB-CAR-T cells, which was highly consistent with the in vitro antitumor activity and proliferation results. Our study provides for the first time a scientific basis for designing OX40-CAR-T cell therapy to improve relapse in patients with MM after CAR-T treatment. [ABSTRACT FROM AUTHOR]