Intratumoral gene editing enhances the effect of tumor immunotherapy

Adoptive T-cell transfer (ACT) therapy is a promising immuno-oncology therapy but is less effective for solid tumors.

In response to this problem, Wei Wei’s team from the State Key Laboratory of Biochemical Engineering of the Institute of Process Engineering of the Chinese Academy of Sciences (hereinafter referred to as the Institute of Process Engineering) and the Pingyuan team of the School of Pharmacy of Zhejiang University carried out cross-collaborative research to activate gene editing of solid tumors through non-invasive means, and regulate the physical and immune microenvironment of solid tumors at the same time, significantly improving the efficacy of a variety of ACT therapies on solid tumors. On May 15, the work was published in Nature Nanotechnology.

Mechanism of action of light/acoustic non-invasive means to activate intratumoral gene-editing synergistic ACT therapy (Photo courtesy of the research team)

ACT therapy reproduces the patient’s own T cells in vitro by taking them back into the patient’s body and then regaining them to recognize and attack tumor cells. However, due to the apoptosis resistance in solid tumor cells to protect it from T cell killing, and the dense physical barrier and immunosuppressive barrier outside solid tumor cells limit the infiltration and killing function of T cells deep into solid tumors, ACT has poor efficacy on most solid tumors. The researchers believe that there is an urgent need to develop new concepts and technologies for the efficiency of solid tumors through interdisciplinary development.

In the newly published work, the research team proposes a new concept of multi-dimensional synergy to improve intracellular apoptosis resistance and extracellular microenvironment. On this basis, they propose to use the thermothermal effect of near-infrared light irradiation (NIR) or focused ultrasound (FUS) non-invasive strategies to activate gene editing to knock out tumor cell anti-apoptotic genes (HSP70 and BAG3), as well as break the physical barrier and immunosuppressive barrier of solid tumors. Through the above synergistic effect, the intratumor infiltration of T cells and the killing effect of tumor cells were significantly enhanced in animal tumor models.

Among them, for superficial tumors, the research team developed a light-driven gene-editing nanodevice (LEGEND), which significantly improved the therapeutic effect of tumor-infiltrating T cells and chimeric antigen receptor T cells, two kinds of adoptive transfusion T cell therapies, tumor infiltrating T cells and chimeric antigen receptor T cells, on mouse tumor models such as melanoma and humanized patient-derived tumor xenograft models. For deep luminal tumors, the research team further developed focused ultrasound-driven gene-editing nanodevices (FUGEND), using the method of “intravenous injection of nanodevices + FUS”, which also demonstrated significant ACT synergistic effects on mouse models of liver cancer in situ.

According to the researchers, the above results are still preclinical studies, and the actual clinical efficacy still needs to be further verified. In view of the versatility and flexibility of the system, different gene editing strategies and non-invasive manipulation methods can be adopted according to different therapeutic needs in the future clinical translation.

Dr. Xiaohong Chen, School of Pharmacy, Zhejiang University, Shuang Wang, associate researcher at the Institute of Process Engineering, and Yuxuan Chen, a doctoral student at the School of Pharmacy, Zhejiang University, are co-first authors of the paper, and Professor Ping Yuan of the School of Pharmacy, Zhejiang University, and Wei Wei, a researcher at the Institute of Process Engineering, are co-corresponding authors. (Source: China Science News Gan Xiao)

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