AsianScientist (Oct. 29, 2020) – Instead of using antibodies to target immune checkpoints, researchers in China have used small hairpin RNA (shRNA) to achieve the same goal. When combined with chemotherapy drugs and an enzyme targeting the tumor microenvironment, the shRNA were able to successfully treat tumors in mice. These findings have been published in Science Advances.
Hailed as one of the most significant breakthroughs in cancer immunotherapy, immune checkpoint blockade has shown dramatic results—but only for certain cancers. While antibodies against CTLA-4 and PD-1 are now available in the clinic, patients using them can sometimes experience severe side effects. One possible reason is that the systemic use of antibodies could over-stimulate the immune system and trigger a harmful response.
To get around this problem, a team led by Professor Tian Huayu from the Changchun Institute of Applied Chemistry of the Chinese Academy of Sciences turned to a different inhibitory technique. Instead of using antibodies specific to PD-1, Tian and the team blocked PD-1 expression using shRNA. In addition to targeting PD-1, they also introduced a plasmid producing hyaluronidase, an enzyme that degrades a key component of the extracellular matrix and is found to be overexpressed in certain tumors. Finally, the team packaged the shRNA, plasmid and the anti-cancer drug doxorubicin into pH-sensitive nanoparticles, which were designed to accumulate in the acidic environment surrounding the tumors.
The combination therapy was found to be more efficient than the traditional combination of chemotherapy and immune checkpoint inhibition, leading to dramatic tumor shrinkage in multiple mouse tumor models. Furthermore, the team also found that the treatment helped to prime tumor-specific T-cells by inducing immunogenic cell death and transforming the tumor microenvironment from immunosuppressive to immune-active.
“These excellent outcomes are mainly attributed to the increasing amount of peripheral CD8+ T-cell infiltration in tumors, which can also induce strong immune memory effects and effectively prevent tumor metastasis,” said Tian.
Although the work has yet to be replicated in humans, it nonetheless presents a promising comprehensive immunotherapy strategy that integrates multiple aspects of regulating the cancer-immunity cycle, including tumor antigen release, T-cell trafficking from the periphery to the tumor, effective killing of tumor cells and the generation of immune memory T-cells.
The article can be found at: Wu et al. (2020) An Immune Cocktail Therapy to Realize Multiple Boosting of the Cancer-immunity Cycle by Combination of Drug/gene Delivery Nanoparticles.
Source: Chinese Academy of Sciences; Photo: Shutterstock.
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