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Acid-Activatable Versatile Micelleplexes for PD-L1 Blockade Enhanced cancer Photodynamic immunotherapy

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Acid-Activatable Versatile Micelleplexes for PD-L1 Blockade ...

Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor

第十二届全国免疫学学术大会

作者： Wang Dangge Wang Tingting Yu Haijun Li Yaping Shanghai Insitute of Materia Medica Chinese Academy of Sciences University of Chinese Academy of Sciences

Photodynamic therapy(PDT) has emerged as a promising clinical modality for cancer therapy due to its ability to initiate an antitumor immune ***,PDT mediated cancer immunotherapy is severely impaired by tumor cell immunosuppression of host T cell antitumor activity through the programmed cell death 1 ligand(PD-L1) and programmed cell death receptor 1(PD-1)(PD-L1-PD-1) immune checkpoint ***,we demonstrate that PDT mediated cancer immunotherapy can be augmented by PD-L1 knockdown(KD) in tumor *** rationally designed a versatile micelleplex by integrating an acid-activatable cationic micelle,photosensitizer(PS),and small interfering RNA(siRNA).The micelleplex was inert at physiological pH conditions and activated only upon internalization in the acidic endocytic vesicles of tumor cells for fluorescence imaging and *** to PDT alone,the combination of PDT and PD-Ll KD showed significantly enhanced efficacy for inhibiting tumor growth and distant metastasis in a B16-F10 melanoma xenograft tumor *** results suggest that acid activatable micelleplexes utilizing PDT-induced cancer immunotherapy are more effective when combined with siRNA-mediated PD-Ll *** study could provide a general strategy for enhancing the therapy efficacy of photodynamic cancer therapy.

关键词： Micelleplexes acid-activatable photodynamic therapy cancer immunotherapy RNA interference

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National Science Review 2024年第4期11卷 206-215页

作者： Ziyan Liao Jie Jiang Wei Wu Jiaqi Shi Yanfang Wang Yuejun Yao Tao Sheng Feng Liu Wei Liu Peng Zhao Feifei Lv Jie Sun Hongjun Li Zhen Gu National Key Laboratory of Advanced Drug Delivery and Release Systems College of Pharmaceutical Sciences Zhejiang University Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province College of Pharmaceutical SciencesZhejiang University Liangzhu Laboratory Zhejiang University Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology Zhejiang University School of Medicine Department of Medical Oncology The First Affiliated Hospital School of Medicine Zhejiang University Department of Laboratory Medicine The First Affiliated Hospital Zhejiang University School of Medicine Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated HospitalSchool of MedicineZhejiang University Jinhua Institute of Zhejiang University MOE Key Laboratory of Macromolecular Synthesis and Functionalization of Ministry of Education Department of Polymer Science and EngineeringZhejiang University Department of General Surgery Sir Run Run Shaw Hospital School of Medicine Zhejiang University

The limited infiltration and persistence of chimeric antigen receptor(CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading,delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

关键词： drug delivery cell therapy bioinspired biomaterials cancer immunotherapy

Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1428-1440页

作者： Youngjoo Lee Sukyung Song Suah Yang Jinseong Kim Yujeong Moon Nayeon Shim Hong Yeol Yoon Sehoon Kim Man Kyu Shim Kwangmeyung Kim KU-KIST Graduate School of Converging Science and Technology Korea UniversitySeoul 02841Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea College of Pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul 03760Republic of Korea Department of Bioengineering Korea UniversitySeoul 02841Republic of Korea

Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced ***,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling ***,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor *** ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV *** 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum ***,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 *** in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 *** ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 ***,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward

关键词： cancer immunotherapy Immune checkpoint blockade PEGylated liposome Crosslinked lipid nanoparticles Anti-PD-L1 peptide Tumor-targeting PD-L1 multivalent binding Lysosomal PD-L1 degradation

PEG400-mediated nanocarriers improve the delivery and therapeutic efficiency of mRNA tumor vaccines

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Chinese Chemical Letters 2024年第5期35卷 314-319页

作者： Wen Xiao Fazhan Wang Yangzhuo Gu Xi He Na Fan Qian Zheng Shugang Qin Zhongshan He Yuquan Wei Xiangrong Song Department of Critical Care Medicine Frontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China Medical Research Center The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhou 450000China

Dendritic cell(DC)-targeted delivery of mRNA is a prominent method to boost the efficacy of mRNA tumor *** targeting ligands are often modified on nanocarriers by polyethylene glycol(PEG)linker in mRNA delivery *** the PEG linker length influences the targeting delivery efficiency of mRNA nanocarrier in vivo remains ***,we designed and constructed DC-targeted mRNA delivery systems modified by mannose via different PEG linker lengths(100/400/1000/2000)(MPn-LPX).The top candidate MP_(400)-LPX(the linker was PEG400)showed the optimal mRNA expression and antigen presentation owing to the highly efficient uptake by ***,MP_(400)-LPX could better inhibited tumor growth and extended survival in the E.G7-OVA lymphoma and TC-1 cervical tumor mouse ***,these results demonstrated that PEG400 was the optimal linker for the PEGylated DC-targeted mRNA *** findings provided a new platform for the rational design of targeted mRNA nanovaccines with shorter-length PEG.

关键词： cancer immunotherapy mRNA vaccines DC-targeted delivery PEGylated liposomes Cellular uptake

Nanomedicine-mediated immunogenic cell death and its combination with immune checkpoint blockade therapy

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Science China Technological Sciences 2024年第8期67卷 2350-2362页

作者： CHEN JunBin ZHANG YuXi SU Miao ZHU YueQiang YANG XianZhu School of Biomedical Sciences and Engineering South China University of TechnologyGuangzhou International Campus National Engineering Research Center for Tissue Restoration and Reconstruction Guangdong Provincial Key Laboratory of Biomedical Engineering Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education South China University of Technology

cancer immunotherapies, which train the natural immune system to specifically kill tumor cells while sparing the healthy cells,have helped revolutionize cancer treatments and demonstrated promising clinical therapeutic benefits for decades. However, the therapeutic outcome of immunotherapies, even for the most successful immune checkpoint blockade(ICB) therapy, remains unsatisfactory in the clinical practice, mainly due to the low immunogenicity of solid tumors and its immunosuppressive tumor microenvironment(TME). Notably, several cancer treatment modalities, including chemotherapy, radiotherapy, and phototherapy, have been revealed to evoke tumor immunogenicity and reverse immunosuppressive TME via inducing immunogenic cell death(ICD) of tumor cells, which synergistically sensitized tumors to ICB therapy. Nanomedicines have been extensively applied to augment ICD-inducing treatment modalities and potentiate ICB therapeutic efficacy therapy due to the opportune convergence of immunotherapy and nanotechnology. Here, we discuss the recent advances in nanomedicine-mediated ICD and its combination with ICB therapy.

关键词： cancer immunotherapy nanomedicine immunogenic cell death immune checkpoint blockade

HER2-based recombinant immunogen to target DCs through FcγRs for cancer immunotherapy

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世界最新医学信息文摘 2015年第5期 7-7页

作者： Ilaria Grazia Zizzari Filippo Veglia Federica Taurino Hassan Rahimi Elena Quaglino Francesca Belleudi Federica Riccardo Morena Antonilli Chiara Napoletano Filippo Bellati Pierluigi Benedetti-Panici Maria Rosaria Torrisi Luigi Frati Marianna Nuti Aurelia Rughetti

Dendritic cell(DC)-based immunotherapy is an attractive approach to induce long lasting antitumor effector cells aiming to control cancer progression. DC targeting is a critical step in the design of DC vaccines in order to optimize delivery and processing of the antigen, and several receptors have been characterized for this purpose. In this study, we employed the FcγRs to target DCs both in vitro and in vivo. We designed a recombinant molecule(HER2- Fc) composed of the immunogenic sequence of the human tumor-associated antigen HER2(aa 364–391) and the Fc domain of a human Ig G1. In a mouse model, HER2-Fc c DNA vaccination activated significant T cell-mediated immune responses towards HER2 peptide epitopes as detected by IFN-γ ELIspot and induced longer tumor latency as compared to Ctrl-Fc-vaccinated control mice. Human in vitro studies indicated that the recombinant HER2-Fc immunogen efficiently targeted human DCs through the FcγRs resulting in protein cross-processing and in the activation of autologous HER2-specific CD8+ T cells from breast cancer patients.

关键词： Dendritic cells cancer immunotherapy HER2 Antigen processing FcγR Dendritic cell targeting

Unlocking T cell exhaustion:Insights and implications for CAR-T cell therapy

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3416-3431页

作者： Dian Xiong Haijun Yu Zhi-Jun Sun State Key Laboratory of Oral&Maxillofacial Reconstruction and Regeneration Key Laboratory of Oral Biomedicine Ministry of EducationHubei Key Laboratory of StomatologySchool&Hospital of StomatologyFrontier Science Center for Immunology and MetabolismTaikang Center for Life and Medical ScienceWuhan UniversityWuhan 430079China Department of Radiation and Medical Oncology Hubei Province Cancer Clinical Study CenterHubei Key Laboratory of Tumor Biological BehaviorsZhongnan Hospital of Wuhan UniversityWuhan 430071China

Chimeric antigen receptor T(CAR-T)cell therapy as a form of adoptive cell therapy(ACT)has shown significant promise in cancer treatment,demonstrated by the FDA-approved CAR-T cell therapies targeting CD19 or B cell maturation antigen(BCMA)for hematological malignancies,albeit with moderate outcomes in solid ***,despite these advancements,the efficacy of CAR-T therapy is often compromised by T cell exhaustion,a phenomenon that impedes the persistence and effector function of CAR-T cells,leading to a relapse rate of up to 75%in patients treated with CD19 or CD22 CAR-T cells for hematological *** to overcome CAR-T exhaustion employ state-of-the-art genomic engineering tools and single-cell sequencing *** this review,we provide a comprehensive understanding of the latest mechanistic insights into T cell exhaustion and their implications for the current efforts to optimize CAR-T cell *** insights,combined with lessons learned from benchmarking CAR-T based products in recent clinical trials,aim to address the challenges posed by T cell exhaustion,potentially setting the stage for the development of tailored next-generation approaches to cancer treatment.

关键词： cancer immunotherapy CAR-T therapy T cell exhaustion Tumor immune microenvironment Spatial immune contexture Single-cell technologies CAR-T engineering Combination therapy

Symphony of nanomaterials and immunotherapy based on the cancer-immunity cycle

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Acta Pharmaceutica Sinica B 2022年第1期12卷 107-134页

作者： Qianqian Li Zhaoqing Shi Fan Zhang Weiwei Zeng Dunwan Zhu Lin Mei School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518107China Tianjin Key Laboratory of Biomedical Materials Key Laboratory of Biomaterials and Nanotechnology for Cancer ImmunotherapyInstitute of Biomedical EngineeringChinese Academy of Medical Sciences&Peking Union Medical CollegeTianjin 300192China

The immune system is involved in the initiation and progression of cancer. Research on cancer and immunity has contributed to the development of several clinically successful immunotherapies. These immunotherapies often act on a single step of the cancer-immunity cycle. In recent years, the discovery of new nanomaterials has dramatically expanded the functions and potential applications of nanomaterials. In addition to acting as drug-delivery platforms, some nanomaterials can induce the immunogenic cell death(ICD) of cancer cells or regulate the profile and strength of the immune response as *** on their versatility, nanomaterials may serve as an integrated platform for multiple drugs or therapeutic strategies, simultaneously targeting several steps of the cancer-immunity cycle to enhance the outcome of anticancer immune response. To illustrate the critical roles of nanomaterials in cancer immunotherapies based on cancer-immunity cycle, this review will comprehensively describe the crosstalk between the immune system and cancer, and the current applications of nanomaterials, including drug carriers, ICD inducers, and immunomodulators. Moreover, this review will provide a detailed discussion of the knowledge regarding developing combinational cancer immunotherapies based on the cancer-immunity cycle, hoping to maximize the efficacy of these treatments assisted by nanomaterials.

关键词： cancer immunotherapy Nanomaterials cancer-immunity cycle Drug delivery ICD inducers Immunomodulators Photothermal therapy Photodynamic therapy Radio sensitizer

Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy of non-microsatellite instability-high colorectal cancer

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Science China(Life Sciences) 2022年第3期65卷 572-587页

作者： Ranran Shi Yubing Li Ling Ran Yu Dong Xiuman Zhou Jingwen Tang Lu Han Mingshuang Wang Liwei Pang Yuanming Qi Yahong Wu Yanfeng Gao School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Sun Yat-sen UniversityShenzhen 518107China Henan Key Laboratory of Bioactive Macromolecules Zhengzhou UniversityZhengzhou 450001China Affiliated cancer Hospital of Zhengzhou University and Henan cancer Hospital Zhengzhou 450008China Department of Integrated Chinse and Western Medicine Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhou 450008China

Colorectal cancer has one of the highest mortality rates among malignant tumors,and most patients with non-microsatellite instability-high (MSI-H) colorectal cancer do not benefit from targeted therapy or immune checkpoint *** of immunogenic neoantigens is a promising strategy for inducing specific antitumor T cells for cancer ***,we screened potential high-frequency neoepitopes from non-MSI-H colorectal cancer and tested their abilities to induce tumorspecific cytotoxic T cell *** HLA-A2-restricted neoepitopes (P31,P50,and P52) were immunogenic and could induce cytotoxic T lymphocytes in peripheral blood mononuclear cells from healthy donors and colorectal cancer *** T lymphocytes induced in HLA-A2.1/K^(b) transgenic mice could recognize and lyse mutant neoepitope-transfected HLA-A2^(+) cancer *** transfer of cytotoxic T lymphocytes induced by the peptide pool of these three neoepitopes effectively inhibited tumor growth and increased the therapeutic effects of anti-PD-1 *** results revealed the potential of high-frequency mutation-specific peptide-based immunotherapy as a personalized treatment approach for patients with non-MSI-H colorectal *** combination of adoptive T cell therapy based on these neoepitopes with immune checkpoint inhibitors,such as anti-PD-1,could provide a promising treatment strategy for non-MSI-H colorectal cancer.

关键词： non-MSI-H colorectal cancer PD-1 neoantigen epitope cancer immunotherapy