A novel immunogene therapy to cancer with high tumor selectivity and safety

ABSTRACT Cancer immunotherapy has made significant advancements over the past few decades, with immune checkpoint and cytokine-based drugs being successfully implemented in clinical settings. Nonetheless, the effective and safe clinical application of these therapies is hindered by critical issues, such as severe toxicity to healthy tissues due to on-target off-tumor effects. In this study, we have developed a novel immunogene therapy characterized by high tumor selectivity and safety in vivo, effectively mitigating the off-tumor effects associated with current antibody-based immune checkpoint therapies. We engineered a gene expression vector that is specifically activated by NF-κB activity to co-express artificial microRNAs targeting two key immune checkpoints (PD-L1 and CD47) and cytokine IL-15. This vector is capable of selectively and effectively down regulating the expression of PDL1 and CD47 while over expressing IL-15 just exclusively in cancer cells, both in vitro and in vivo. Through this mechanism, both adaptive and innate immune responses can be simultaneously activated and enhanced via the transfection of this vector. The in vivo administration of this vector via recombinant adeno-associated virus (AAV) demonstrated significant antitumor activity, high tumor selectivity, and safety in murine models. Consequently, this vector may offer a potential more effective and safer alternative to the current immune checkpoint inhibitors in future clinical applications.