CHEMICAL SCIENCE

Non-invasive activation of intratumoral gene-editing synergistic T cell therapy


Adoptive T-cell transfer (ACT) therapy is a promising tumor immunotherapy, but it is not effective on solid tumors, and it is urgent to develop new concepts and technologies for solid tumor synergy through interdisciplinary development.

On May 15, 2023, the Pingyuan team of the School of Pharmacy of Zhejiang University and the Wei Wei team of the State Key Laboratory of Biochemical Engineering of the Institute of Process Engineering, Chinese Academy of Sciences published a paper entitled “Non-Invasive Activation of Intratumoural Gene Editing for Improved Adoptive T-Cell Therapy in” in the journal Nature Nanotechnology Solid Tumours”, a research paper that develops a non-invasive gene editing technology that activates apoptosis-resistant gene editing in solid tumors by non-invasive means (near-infrared light or focused ultrasound), and regulates the physical and immune microenvironment of solid tumors, significantly improving the efficacy of multiple ACT therapies for solid tumors.

Dr. Xiaohong Chen, School of Pharmacy, Zhejiang University, Wang Shuang, associate researcher at the Institute of Process Engineering, Chinese Academy of Sciences, 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, Chinese Academy of Sciences, are co-corresponding authors.

Currently, cancer is one of the most common fatal diseases worldwide. Traditional cancer treatments include surgery, radiation and chemotherapy, but these have limitations. For example, surgery may not completely remove tumor tissue; Radiation and chemotherapy can cause damage to healthy cells. In recent years, adoptive T-cell transfer (ACT) immunotherapy and genome editing therapy have become emerging directions in the field of cancer treatment. However, the effect of cellular immunotherapy is affected by the apoptosis resistance mechanism of tumor cells and the tumor microenvironment, while gene editing technology needs to achieve genome editing by delivering CRISPR/Cas9, which also has certain limitations.

In view of this, the Pingyuan team of the School of Pharmacy of Zhejiang University and the team of Wei Wei of the Institute of Process Engineering of the Chinese Academy of Sciences have developed a non-invasive gene editing technology that can activate the apoptosis-resistant gene editing of solid tumors through non-invasive means (near-infrared light or focused ultrasound), and regulate the physical and immune microenvironment of solid tumors, significantly improving the efficacy of multiple ACT therapies on solid tumors.

Figure 1: Mechanism of action of light/acoustic non-invasive means to activate intratumoral gene-editing synergistic ACT therapy.

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, the microenvironment limits the infiltration and killing function of T cells into the depths of solid tumors, resulting in the poor efficacy of ACT therapy for most solid tumors.

In the face of these challenges, Professor Pingyuan’s team has carried out cross-collaborative research based on years of research experience in gene editing delivery and regulation, and Wei Wei’s team based on their deep research foundation in tumor immunotherapy and biodosage form engineering. Based on the new concept of multi-dimensional synergy to improve intracellular apoptosis resistance and extracellular microenvironment, the two parties proposed to use the thermothermal effect of NIR irradiation or focused ultrasound FUS non-invasive strategies to activate gene editing to knock out tumor cell anti-apoptotic genes (HSP70 and BAG3), and break the physical barrier and immunosuppressive barrier of solid tumors at the same time. 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.

Figure 2. The LEGEND system improves intracellular apoptosis resistance and extracellular microenvironment in multiple dimensions, and enhances the therapeutic effect of TIL therapy. a. LEGEND+NIR irradiation activates intratumor gene editing and knocks out tumor cell anti-apoptotic genes (HSP70 and BAG3); b-d. The NIR warming effect breaks down the physical barriers of solid tumors, including accelerated blood flow (b), decreased interstitial pressure (c), tissue loosening (d); e. NIR warming effect improves tumor immunosuppressive microenvironment; f. LEGEND treatment significantly enhances intratumoral invasion of TIL; After g,h LEGEND treatment, the tumor inhibitory effect of TIL infusion therapy was significantly improved.

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.

In the past three years, Professor Pingyuan of the School of Pharmacy of Zhejiang University has developed a variety of non-viral vectors for the delivery of gene editing tools, and has been successfully used in animal models for the treatment of tumors and inflammatory diseases. Related work has been published in PNAS. 2020, 117, 2395-2405、Sci. Adv. 2021, 7, eabj0624、Sci. Adv. 2021, 7, eabe2888、Adv. Mater. 2021, 2006003、ACS Cent. Sci. 2021, 7, 990-1000、Nano Lett. 2021, 21, 9761-9771、Signal Transduct. Target. Ther. 2022, 7, 269 and Sci. Adv. 2022, 8, ABP9435 and other journals.

In the past five years, Wei Wei, a researcher from the team of Academician Ma Guanghui of the State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, has created a series of new dosage forms for drug and vaccine delivery, which have been successfully used in animal models for the prevention and treatment of tumors, infectious diseases and inflammatory diseases, and some dosage forms have been approved by hospital ethics to enter individualized preclinical and clinical research. Related work has been published in Nat Nanotechnol 2021, 16, 1413, Sci Transl Med 2021, 13, eabb6981, Nat Biomed Eng 2023, accepted, Nat Biomed Eng 2021, 5, 414, Nat Biomed Eng 2021, 5, 968, Sci Adv 2021, 7, eabd7614, Sci Adv 2021, 7, eaba2458, Sci Adv 2020, 6, eaay7735, Sci Adv 2019, 5, eaaw3192, Nat Commun 2022, 13, 4214, Nat Commun 2021, 12, 6399, Nat Commun 2019, 10, 5165, Nat Commun 2017, 8, 14537, etc.

This work was supported by the National Key Research and Development Program of China, the National Natural Science Foundation of China and the Natural Science Foundation of Zhejiang Province. (Source: Science Network)

Related paper information:https://doi.org/10.1038/s41565-023-01378-3



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