Advanced Materials Liu Mi's team from Soochow University reconstituted whole-cell components of cancer cells or tumor tissues into nano-vaccine, which can effectively prevent and treat a variety of cancers

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iNature cancer vaccine is one of the main methods of cancer immunotherapy and prevention
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Cancer cells and tumor tissues contain various cancer-specific and cancer-related mutations and neo-antigens (Neo-antigens), so cancer cells and tumor tissues themselves, especially cancer cells and whole cell components of tumor tissues, are the best antigen libraries It is also the best antigen raw material for preparing preventive and therapeutic cancer vaccines
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On September 18, 2021, Liu Mi, Department of Pharmacy, School of Pharmacy, Soochow University, as the corresponding author, published an online publication titled "Immunotherapy and Prevention of Cancer by Nanovaccines Loaded with Whole-Cell Components of Tumor Tissues or Cells" in Advanced Materials (IF=30.
85) The research paper (Featured), invented a method for preparing preventive and therapeutic cancer vaccines that can be used in all types of cancer
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This method reassembles the whole cell components of cancer cells or tumor tissues into nano-scale nano-vaccine through PLGA nanoparticles
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This paper is also listed as a hot topic in drug delivery
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The whole-cell genome analysis or proteomic analysis of cancer cells that has emerged in recent years can find neo-antigens (Neo-antigens) produced by mutations in certain cancer cells through comparative analysis with healthy cells, and personalized customized vaccines prepared using these antigens It has shown good therapeutic effects in clinical trials
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However, the above-mentioned vaccines are time-consuming, labor-intensive, and expensive, and a patient can only find a limited number of neoantigens, and the number of cancer cells analyzed is limited, and there are great differences between cancer cells in the tumor tissue, so its clinical application and treatment The effect is limited
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Figure 1 (a) Schematic diagram of reorganizing whole cell components of cancer cells or tumor tissue into nano-vaccine; (b) Preparation scheme of reorganizing whole-cell components of cancer cell or tumor tissue into nano-vaccine; (c) Nano vaccine causes cancer Diagram of the mechanism of cell-specific immune response
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The more types of cancer antigens a cancer vaccine carries, the more extensive the cancer-specific immune response that the vaccine can stimulate, and the better the vaccine's effect
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Although cancer cells or tumor tissues include all cancer neoantigens and are the best vaccine preparation materials, due to the limitations of traditional vaccine preparation techniques, we cannot prepare cancer vaccines with whole cell components
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This is mainly due to the fact that in addition to the water-soluble components, there are many non-water-soluble components in the whole cell components.
The insoluble components are insoluble in water and common organic solvents, which make them unable to be loaded into the vaccine dosage form.
Effective drug delivery
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However, these large amounts of non-water-soluble components (such as membrane proteins) in cells contain many cancer-specific and cancer-related mutations and neo-antigens (Neo-antigens), which makes traditional vaccine preparation methods unable to maximize cancer vaccines.
The effect of
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In this study, 8M urea was used to solubilize the non-water-soluble components produced by the lysis of cancer cells or tumor tissues, and both the water-soluble components and the non-water-soluble components were loaded into the nano-vaccine, so that the cancer cells or tumor tissues were successfully The whole cell components of the virus were reconstituted into a nano-vaccine (Figure 1a and b)
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Figure 2 Experimental results of nano-vaccine to prevent lung cancer and melanoma
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(A) Time schedule of vaccine administration and tumor inoculation when nano-vaccine prevents lung cancer in mouse model; (b) Growth curve of lung cancer tumor when nano-vaccine prevents lung cancer in mouse model; (c) Nano-vaccine prevention in mouse model Survival curve of mice with lung cancer; (d) Time schedule of vaccine administration and tumor inoculation when nano-vaccine prevents melanoma in mouse model; (e) Tumor growth curve of melanoma when nano-vaccine prevents melanoma in mouse model (F) The survival curve of mice when the nano-vaccine prevents melanoma in the mouse model
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In order to maximize the loading of cancer antigens, whole cell components are loaded on the inside and the surface of the nano-vaccine at the same time
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In order to increase the efficacy of the vaccine, the immune adjuvant is co-loaded with the whole cell component in the nano-vaccine, which greatly enhances the ability of the nano-vaccine to activate antigen-specific T cells
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Antigen-presenting cells (APCs) like to swallow nano-scale substances, so nano-vaccines are more likely to be swallowed by antigen-presenting cells and activate cancer-specific immune responses (Figure 1c)
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The results of cancer prevention experiments show (Figure 2) that the nano-vaccine prepared in this research can effectively prevent lung cancer (100%) and melanoma (70%) in mice
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Figure 3 Experimental results of nano-vaccine in the treatment of melanoma in a mouse model
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(A) Nano vaccine administration schedule; (b) and (d) tumor growth curve; (c) and (e) mouse survival curve; (f) tumor growth curve after the second inoculation of cured mice tumor and ( g) Survival curve; (h) Dosing schedule of nano-vaccine and αPD-1 combination therapy; (i) and (k) tumor growth curve during combination therapy; (j) and (l) survival curve during combination therapy
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The results of the cancer therapeutic experiment found (Figure 3) that the nano-vaccine can effectively treat melanoma and triple-negative breast cancer in mice, and can cure some mice (25%)
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The PD-1 antibody can increase the cure rate of the nano-vaccine treatment of melanoma tumor-bearing mice to 40%
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In addition, metformin can further improve the therapeutic effect of nano-vaccine
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Figure 4.
T cell and tumor microenvironment analysis of mice after nanovaccine treatment
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(A) Multiply CD3 (T cells), CD11c (dendritic cells), B220 (B cells), F4/80 (macrophages), CD49b (NK cells) and DAPI (nucleus) on the tumor tissue after treatment Fluorescence immunohistochemical detection; (b) Multiple fluorescence immunohistochemical detection of CD3, CD4, CD8, FOXP3, IFN-γ and DAPI on tumor tissue after treatment; (c) F4/80, CD163 on tumor tissue after treatment Multiple fluorescence immunohistochemical detection of, CD80, PD-1, PD-L1, DAPI; (d) and (e) cancer cell antigen-specific CD8+ T cells and CD4+ T cells in the spleen of mice after nanovaccine immunotherapy Content analysis
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By analyzing the T cells and tumor microenvironment of the mice immunized by the nano-vaccine (Figure 4), the study found that the nano-vaccine can efficiently induce tumor-specific T cells and activate the adaptive and innate immune response to tumor cells at the same time
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Fluorescence multi-target immunoassay analysis shows (Figure 5) that the nano-vaccine promotes the formation of tertiary lymphatic structure in the tumor site by increasing the content of immune cells, especially B cells, in the tumor microenvironment.
The formation of high-grade lymphatic structure is critical to the effect of cancer immunotherapy
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Figure 5.
B cell aggregation and tertiary lymphatic structure formed by various immune cells in the tumor microenvironment of mouse melanoma after nanovaccine treatment
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CD3 (T cell), CD11c (dendritic cell), B220 (B cell), F4/80 (macrophage), CD49b (NK cell) and DAPI (nucleus)
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In addition, the nano-vaccine increased the content of central memory T cells (Tcm), effector memory T cells (Tem) and tissue-resident memory T cells (Trm) in mice
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In this way, the mice have long-term immune memory that can recognize and kill cancer cells
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The steps of preparing the nano-vaccine in this study are simple and can be completed in one or a few days (depending on whether freeze-drying is required)
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The PLGA and urea used in the preparation of the nano-vaccine are all pharmaceutical excipients approved by the FDA, and the prepared nano-vaccine has a simple dosage form
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These advantages make the nano vaccine safer and convenient for clinical transformation and application
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And because the nano-vaccine has a simple dosage form, it is convenient for production and quality control of the production process
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In short, this research has discovered a universal method for preparing cancer vaccines, which can produce nano-vaccine based on cancer cells or tumor tissues.
The nano-vaccine can be used for cancer immunotherapy to prevent the occurrence, recurrence and metastasis of cancer
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Liu Mi's research group has applied for more than 10 international and domestic invention patents for the preparation method of the nano-vaccine, related vaccine system and pharmaceutical dosage system
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Subsequent related research results are being submitted
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Link to the article: https://onlinelibrary.
wiley.
com/doi/10.
1002/adma.
202104849 Introduction to the corresponding author: Liu Mi, professor of the Department of Pharmacy, School of Pharmacy, Soochow University, graduated with a master's degree from Peking University School of Pharmacy in 2010, and Swiss Federal Institute of Technology in Zurich in 2014 ( Graduated from the Pharmacy Department of the School of Pharmacy, ETH Zürich
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He started as a postdoctoral fellow in the Department of Immunology of Harvard Medical School in November 2014
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In December 2018, he joined the Department of Pharmacy of Soochow University School of Pharmacy as a distinguished professor and doctoral supervisor
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Mainly engaged in the research of preventive and therapeutic cancer vaccines, new coronavirus therapeutic neutralizing antibodies, mRNA vaccines, probiotics and immune multi-target detection technologies
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Won the Mary K.
Iacocca Fellowship of Harvard Medical School twice, and published many papers in world-class journals such as Nature Communications, Advanced Materials, Advanced Functional Materials, Progress in Polymer Science as the corresponding author or first author, and has applied for prevention and treatment There are more than 20 international patents and domestic patents such as sexual cancer vaccines, new coronavirus neutralizing antibodies, and immune multi-target detection technologies
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