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Fully synthetic Tn-based three-component cancer vaccine using covalently linked TLR4 ligand MPLA and iNKT cell agonist KRN-7000 as built-in adjuvant effectively protects mice from tumor development

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Acta Pharmaceutica Sinica B 2022年第12期12卷 4432-4445页

作者： Deying Yang Xiang Luo Qinghai Lian Lingqiang Gao Chengxin Wang Xiaoxiao Qi Rong Zhang Zhongqiu Liu Guochao Liao Joint Laboratory for Translational cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China International Institute for Translational Chinese MedicineGuangzhou University of Chinese MedicineGuangzhou 510006China Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research Guangzhou 510120China

We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier *** Tn antigen as the model,a three-component vaccine(MPLA-Tn-KRN7000)containing the TLR4 ligand MPLA and the iNKT cell agonist KRN7000 was designed and *** expands fully synthetic self-adjuvanting vaccine studies that use a single carrier to one with two different types of *** corresponding two-component conjugate vaccines Tn-MPLA,Tn-KRN7000 and Tn-CRM197 were also synthesized,as *** immunological evaluation found that MPLA-Tn-KRN7000 elicits robust Tn-specific and T cell-dependent *** antibodies specifically recognized,bound to and exhibited complement-dependent cytotoxicity against Tn-positive cancer *** addition,MPLA-Tn-KRN7000 increased the survival rate and survival time of tumor-challenged mice,and surviving mice reject further tumor attacks without any additional *** to the glycoprotein vaccine Tn-CRM197,the two-component conjugate vaccines,Tn-MPLA and Tn-KRN7000,and the physical mixture of Tn-MPLA and Tn-KRN7000,MPLA-Tn-KRN7000 showed the most effect at combating tumor cells both in vitro and in *** comparison of immunological studies in wild-type and TLR4 knockout mice,along with the test of binding affinity to CD1d protein suggests that the covalently linked MPLA-KRN7000 immunostimulant induces a synergistic activation of TLR4 and iNKT cell that improves the immunogenicity of *** work demonstrates that MPLA-Tn-KRN7000 has the potential to be a vaccine candidate and provides a new direction for fully synthetic vaccine design.

关键词： cancer vaccine Tn antigen MPLA KRN7000 Immunotherapy

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Generated SecPen_NY-ESO-1_ubiquitin-pulsed dendritic cell cancer vaccine elicits stronger and specific T cell immune responses

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Acta Pharmaceutica Sinica B 2021年第2期11卷 476-487页

作者： Yunkai Yang Xiaohan Guo Bo Hu Peng He Xiaowu Jiang Zuohuan Wang Huaxing Zhu Lina Hu Minghua Yu Meiqing Feng Shanghai Engineering Research Center of ImmunoTherapeutics School of PharmacyFudan UniversityShanghai 201203China Shanghai Novoprotein Biotechnology Co. Ltd.Shanghai 201203China Medical School of Yichun University Yichun 336000China Clinical Research Center 2nd Affiliated HospitalMedical College of Zhejiang UniversityHangzhou 310009China Department of Oncology Shanghai Pudong HospitalFudan University Pudong Medicine CenterShanghai 201399China

Dendritic cell-based cancer vaccines(DC vaccines)have been proved efficient and safe in immunotherapy of various cancers,including melanoma,ovarian and prostate ***,the clinical responses were not always *** we proposed a novel strategy to prepare DC *** the present study,a fusion protein SNU containing a secretin-penetratin(SecPen)peptide,NY-ESO-1 and ubiquitin was designed and *** establish the DC vaccine(DC-SNU),the mouse bone marrowderived DCs(BMDCs)were isolated,pulsed with SNU and maturated with cytokine *** peripheral blood mononuclear cells(PBMCs)from C57 BL/6 mice inoculated intraperitoneally with DCSNU were separated and cocultured with MC38/MC38NY-ESO-1 tumor cells or DC *** results show that SNU was successfully *** strategy made NY-ESO-1 entering cytoplasm of BMDCs more efficiently and degraded mainly by *** we expected,mature BMDCs expressed higher CD40,CD80 and CD86 than immature ***,the PBMCs released more IFN-γand TNF-αwhen stimulated with DC-SNU in vitro ***’s more,the PBMCs induced stronger and specific cytotoxicity towards MC38NY-ESO-1 tumor *** the above,it demonstrated that DC-SNU loaded with SecPen and ubiquitin-fused NY-ESO-1 could elicit stronger and specific T cell immune *** strategy can be used as a platform for DC vaccine preparation and applied to various cancers treatment.

关键词： Dendritic cells cancer vaccine NY-ESO-1 SecPen Ubiquitin

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Cyclophosphamide loaded thermo-responsive hydrogel system synergize with a hydrogel cancer vaccine to amplify cancer immunotherapy in a prime-boost manner

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Bioactive Materials 2021年第10期6卷 3036-3048页

作者： Fan Yang Kun Shi Ying Hao Yanpeng Jia Qingya Liu Yu Chen Meng Pan Liping Yuan Yongyang Yu Zhiyong Qian State Key Laboratory of Biotherapy and cancer Center Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengdu610041PR China Department of Gastrointestinal Surgery West China HospitalSichuan UniversityChengdu610041PR China

Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity,their development is hindered by the limitations of neoantigens identification,low immunogenicity,and weak immune ***(CTX)not only directly kills tumors but also causes immunogenic cell death,providing a promising source of antigens for cancer ***,a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is ***,CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity,and then 3 days later,PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune *** results confirm that this combined strategy reduces the toxicity of CTX,and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth,prolong survival,and significantly improve the tumor cure ***,a long-lasting immune memory response is observed in the *** 90%of the cured mice survive for at least 60 days after being re-inoculated with tumors,and the distant tumor growth is also well ***,this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines.

关键词： Immunotherapy Thermo-responsive hydrogels Immunogenic cell death cancer vaccine Cyclophosphamide

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Impact of 5-Fu/oxaliplatin on mouse dendritic cells and synergetic effect with a colon cancer vaccine

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Chinese Journal of cancer Research 2018年第2期30卷 197-208页

作者： Xinqiang Hong Tiangeng Dong Tuo Yi Jianwei Hu Zhen Zhang Shengli Lin Weixin Niu Department of General Surgery Zhongshan Hospital Fudan University

Objective： The aim of the present study was to investigate the effects of 5-fluorouracil（5-Fu） and oxaliplatin on the function and activation pathways of mouse dendritic cells（DCs）, and to clarify whether 5-Fu/oxaliplatin combined with the CD1d-MC38/α-galactosylceramide（α-GC） tumor vaccine exhibits synergistic effects on the treatment of colon cancer in ***： The combination of the Toll like receptor（TLR） ligands and/or 5-Fu/oxaliplatin was added into myeloid-derived DCs in vitro culture. DC phenotypic changes were detected by flow cytometry, and the secretion of DC cytokines was detected by cytometric bead array（CBA）. A MC38 mouse colon cancer model was constructed and the DCs were isolated from the spleen, tumor tissue and lymph nodes following intraperitoneal injection of 5-Fu/oxaliplatin. The cell phenotypes were detected by flow cytometry. The tumor infiltrating leukocytes,splenocytes and lymph node cells were co-cultured with the dead MC38 tumor cells, and the secretion levels of interferon-γ（IFN-γ） were detected. 5-Fu/oxaliplatin combined with our previously developed CD1d-MC38/α-GC tumor vaccine was used to inhibit the growth of MC38 colon cancer in mice, and the tumor growth rate and survival time were ***： 5-Fu/oxaliplatin exerted no significant effect on the expression of the stimulating phenotypes of DCs in vitro, while it could reduce the expression of programmed death ligand 1/2（PD-L1/L2） and promote interleukin-12（IL-12） secretion by DCs. Furthermore 5-Fu/oxaliplatin was beneficial to the differentiation of T-helper 1（Th1） cells. 5-Fu/oxaliplatin further enhanced the stimulating phenotypic expression of DCs in tumor bearing mice, decreased PD-L1/L2 expression, and specifically activated the lymphocytes. The CD1d-MC38/α-GC tumor vaccine combined with 5-Fu/oxaliplatin could exert a synergistic role that resulted in a significant delay of the tumor growth rate, and an increase in the survival time of tumor bearing ***： 5

关键词： Dendritic cell colon cancer cancer vaccine chemoimmunotherapy

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IL-27 local and systemic delivery induces anti-tumor immunity via different mechanisms: implications for the design of IL-27-based cancer vaccine

IL-27 local and systemic delivery induces anti-tumor immunit...

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第十一届全国免疫学学术大会

作者： Zhu Jianmin Zhu Hua Shi Min Bai Xue-Feng Pediatric Translational Medicine Institute Shanghai Children’s Medical Center Shanghai Jiaotong University School of Medicine

IL-27 is an anti-inflammatory cytokine with potent antitumor *** using preclinical mouse models have revealed that IL-27 exert its antitumor activity via various mechanisms including induction of anti-tumor T cell *** determine if IL-27 has the potential to be used as a cancer vaccine or vaccine adjuvant,we first generated IL-27-secreting B16.F10 cells(B16-IL-27)and compared B16-IL-27 with GM-CSF-secreting B16.F10 cells

关键词： IL-27 antitumor activity cancer vaccine adjuvant

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Synthesis of DNP-modified GM3-based anticancer vaccine and evaluation of its immunological activities for cancer immunotherapy

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Chinese Chemical Letters 2021年第12期32卷 4041-4044页

作者： Han Lin Haofei Hong Lipeng Feng Jie Shi Zhifang Zhou Zhimeng Wu Key Laboratory of Carbohydrate Chemistry&Biotechnology Ministry of EducationSchool of BiotechnologyJiangnan UniversityWuxi 214122China

Tumor-associated carbohydrate antigens(TACAs) are attractive targets for vaccine development. In this context, we described a strategy combining artificial TACA and glycoengineering for cancer vaccine development. A 2,4-ditrophenyl(DNP)-modified GM3 intermediate was synthesized chemoenzymatically and conjugated to keyhole limpet hemocyanin(KLH), and the resulting bioconjugate was tested for its potential as a vaccine candidate. Mice immunological studies revealed that the DNP-modified GM3(GM3-NHDNP) analog elicited strong and rapid immune responses by recruiting anti-DNP antibodies to facilitate the targeted delivery of the vaccine construct to antigen processing cells(APCs). Moreover, the endogenously produced anti-DNP antibodies, together with the elicited antibodies against GM3-NHDNP, may synergistically promote tumor binding and cancer cell death when the cancer cell surfaces are glycoengineered to express the GM3-NHDNP antigen.

关键词： GM3 cancer vaccine Anti-DNP antibodies Glycoengineering Tumor-associated carbohydrate antigen

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Personalized pancreatic cancer therapy:from the perspective of mRNA vaccine

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Military Medical Research 2023年第4期10卷 461-477页

作者： Xing Huang Gang Zhang Tian‑Yu Tang Xiang Gao Ting‑Bo Liang Zhejiang Provincial Key Laboratory of Pancreatic Disease the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Department of Hepatobiliary and Pancreatic Surgery the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases Hangzhou 310003China The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province Hangzhou 310009China cancer Center Zhejiang UniversityHangzhou 310058China

Pancreatic cancer is characterized by inter-tumoral and intra-tumoral heterogeneity,especially in genetic alteration and *** therapeutic strategies for pancreatic cancer usually suffer resistance,highlighting the necessity for personalized precise *** vaccines have become promising alternatives for pancreatic cancer treatment because of their multifaceted advantages including multiple targeting,minimal nonspecific effects,broad therapeutic window,low toxicity,and induction of persistent immunological *** conventional vaccines based on the cells,microorganisms,exosomes,proteins,peptides,or DNA against pancreatic cancer have been developed;however,their overall efficacy remains *** with these vaccine modalities,messager RNA(mRNA)-based vaccines offer technical and conceptional advances in personalized precise treatment,and thus represent a potentially cutting-edge option in novel therapeutic approaches for pancreatic *** review summarizes the current progress on pancreatic cancer vaccines,highlights the superiority of mRNA vaccines over other conventional vaccines,and proposes the viable tactic for designing and applying personalized mRNA vaccines for the precise treatment of pancreatic cancer.

关键词： Pancreatic cancer Precise therapy cancer vaccine mRNA vaccine Tumor antigen Immune subtype

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Genetically-engineered“all-in-one”vaccine platform for cancer immunotherapy

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3622-3635页

作者： Aihua Wu Yingzhi Chen Hairui Wang Ya Chang Meng Zhang Pengfei Zhao Yisi Tang Qin Xu Zhuangzhi Zhu Yang Cao Yongzhuo Huang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Artemisinin Research Center the First Affiliated HospitalGuangzhou University of Chinese MedicineGuangzhou 510450China National Pharmaceutical Engineering Research Center China State Institute of Pharmaceutical IndustryShanghai 201203China Zhongshan Institute for Drug Discovery Institutes of Drug Discovery and DevelopmentChinese Academy of SciencesZhongshan 528437China University of Chinese Academy of Sciences Beijing 100049China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients Shanghai 201203China

An essential step for cancer vaccination is to break the immunosuppression and elicit a tumor-specific immunity.A major hurdle against cancer therapeutic vaccination is the insufficient immune stimulation of the cancer vaccines and lack of a safe and efficient adjuvant for human *** discovered a novel cancer immunostimulant,trichosanthin(TCS),that is a clinically used protein drug in China,and developed a well-adaptable protein-engineering method for making recombinant protein vaccines by fusion of an antigenic peptide,TCS,and a cell-penetrating peptide(CPP),termed an"allin-one"vaccine,for transcutaneous cancer *** TCS adjuvant effect on antigen presentation was investigated and the antitumor immunity of the vaccines was investigated using the different tumor *** vaccines were prepared via a facile recombinant *** vaccines induced the maturation of DCs that subsequently primed CD8^(+)T *** TCS-based immunostimulation was associated with the STING *** general applicability of this genetic engineering strategy was demonstrated with various tumor antigens(i.e.,legumain and TRP2 antigenic peptides)and tumor models(i.e.,colon tumor and melanoma).These findings represent a useful protocol for developing cancer vaccines at low cost and time-saving,and demonstrates the adjuvant application of TCSdan old drug for a new application.

关键词： Trichosanthin Legumain TRP2 Transcutaneous immunization Adjuvant cancer vaccine Protein engineering

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Engineering cancer vaccines using stimuli-responsive biomaterials

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Nano Research 2018年第10期11卷 5355-5371页

作者： Yu Zhao Yugang Guo Li Tang Institute of Bioengineering Ecole polytechnique federale de Lausanne (EPFL) Lausanne CH-1015 Switzerland Institute of Materials Science & Engineering Ecole polytechnique federale de Lausanne (EPFL) Lausanne CH- 1015 Switzerland

cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison to other immunotherapies, such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges need to be overcome to develop a highly efficient and safe delivery strategy for targeting cancer vaccines to professional antigen-presenting cells and eliciting optimized immune response against cancers. To meet these challenges, biomaterials, particularly biomaterials that are designed to respond to certain environmental stimuli, termed as stimuli-responsive biomaterials, are being actively developed to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines while focusing on the chemistry and material design with varied responsiveness. We also discuss the present challenges and opportunities in the field and provide a perspective for future directions.

关键词： cancer vaccine stimuli-responsive biomaterial nanoparticle immune response lymph node targeting cross-presentation

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mRNA cancer vaccines:Advances,trends and challenges

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Acta Pharmaceutica Sinica B 2022年第7期12卷 2969-2989页

作者： Qing He Hua Gao Dejiang Tan Heng Zhang Jun-zhi Wang National Institutes for Food and Drug Control State Key Laboratory for Evaluation and Standardization of Innovative Vaccines and Biotechnology ProductsBeijing 102629China

Patients exhibit good tolerance to messenger ribonucleic acid(m RNA)vaccines,and the choice of encoded molecules is flexible and *** vaccines can be engineered to express full-length antigens containing multiple epitopes without major histocompatibility complex(MHC)restriction,are relatively easy to control and can be rapidly mass *** 2021,the *** and Drug Administration(FDA)approved the first m RNA-based coronavirus disease 2019(COVID-19)vaccine produced by Pfizer and Bio NTech,which has generated enthusiasm for m RNA vaccine research and *** on the above characteristics and the development of m RNA vaccines,m RNA cancer vaccines have become a research hotspot and have undergone rapid development,especially in the last five *** review analyzes the advances in m RNA cancer vaccines from various perspectives,including the selection and expression of antigens/targets,the application of vectors and adjuvants,different administration routes,and preclinical evaluation,to reflect the trends and challenges associated with these vaccines.

关键词： mRNA cancer vaccine Tumor-associated antigens Neoantigens mRNA delivery vectors Adjuvants Administration routes

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