Molecular Therapy Oncolytics最新文献_第5页

Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives. 基因疗法治疗胃肠道疾病的潜力：进展与未来展望。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-08-18 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.007

Ning-Ning Yue, Hao-Ming Xu, Jing Xu, Min-Zheng Zhu, Yuan Zhang, Cheng-Mei Tian, Yu-Qiang Nie, Jun Yao, Yu-Jie Liang, De-Feng Li, Li-Sheng Wang

{"title":"Therapeutic potential of gene therapy for gastrointestinal diseases: Advancements and future perspectives.","authors":"Ning-Ning Yue, Hao-Ming Xu, Jing Xu, Min-Zheng Zhu, Yuan Zhang, Cheng-Mei Tian, Yu-Qiang Nie, Jun Yao, Yu-Jie Liang, De-Feng Li, Li-Sheng Wang","doi":"10.1016/j.omto.2023.08.007","DOIUrl":"10.1016/j.omto.2023.08.007","url":null,"abstract":"Advancements in understanding the pathogenesis mechanisms underlying gastrointestinal diseases, encompassing inflammatory bowel disease, gastrointestinal cancer, and gastroesophageal reflux disease, have led to the identification of numerous novel therapeutic targets. These discoveries have opened up exciting possibilities for developing gene therapy strategies to treat gastrointestinal diseases. These strategies include gene replacement, gene enhancement, gene overexpression, gene function blocking, and transgenic somatic cell transplantation. In this review, we introduce the important gene therapy targets and targeted delivery systems within the field of gastroenterology. Furthermore, we provide a comprehensive overview of recent progress in gene therapy related to gastrointestinal disorders and shed light on the application of innovative gene-editing technologies in treating these conditions. These developments are fueling a revolution in the management of gastrointestinal diseases. Ultimately, we discuss the current challenges (particularly regarding safety, oral efficacy, and cost) and explore potential future directions for implementing gene therapy in the clinical settings for gastrointestinal diseases.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"193-215"},"PeriodicalIF":5.3,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10471515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10153197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Endogenous H3.3K27M derived peptide restricted to HLA-A∗02:01 is insufficient for immune-targeting in diffuse midline glioma. 局限于HLA-A*02:01的内源性H3.3K27M衍生肽不足以用于弥漫性中线神经胶质瘤的免疫靶向。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-08-15 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.08.005

Stacie S Wang, Kirti Pandey, Katherine A Watson, Rebecca C Abbott, Nicole A Mifsud, Fiona M Gracey, Sri H Ramarathinam, Ryan S Cross, Anthony W Purcell, Misty R Jenkins

{"title":"Endogenous H3.3K27M derived peptide restricted to HLA-A∗02:01 is insufficient for immune-targeting in diffuse midline glioma.","authors":"Stacie S Wang, Kirti Pandey, Katherine A Watson, Rebecca C Abbott, Nicole A Mifsud, Fiona M Gracey, Sri H Ramarathinam, Ryan S Cross, Anthony W Purcell, Misty R Jenkins","doi":"10.1016/j.omto.2023.08.005","DOIUrl":"10.1016/j.omto.2023.08.005","url":null,"abstract":"Diffuse midline glioma (DMG) is a childhood brain tumor with an extremely poor prognosis. Chimeric antigen receptor (CAR) T cell therapy has recently demonstrated some success in DMG, but there may a need to target multiple tumor-specific targets to avoid antigen escape. We developed a second-generation CAR targeting an HLA-A∗02:01 restricted histone 3K27M epitope in DMG, the target of previous peptide vaccination and T cell receptor-mimics. These CAR T cells demonstrated specific, titratable, binding to cells pulsed with the H3.3K27M peptide. However, we were unable to observe scFv binding, CAR T cell activation, or cytotoxic function against H3.3K27M+ patient-derived models. Despite using sensitive immunopeptidomics, we could not detect the H3.3K27M26-35-HLA-A∗02:01 peptide on these patient-derived models. Interestingly, other non-mutated peptides from DMG were detected bound to HLA-A∗02:01 and other class I molecules, including a novel HLA-A3-restricted peptide encompassing the K27M mutation and overlapping with the H3 K27M26-35-HLA-A∗02:01 peptide. These results suggest that targeting the H3 K27M26-35 mutation in context of HLA-A∗02:01 may not be a feasible immunotherapy strategy because of its lack of presentation. These findings should inform future investigations and clinical trials in DMG.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"167-180"},"PeriodicalIF":5.7,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c4/79/main.PMC10477804.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10550711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oncolytic virus-driven immune remodeling revealed in mouse medulloblastomas at single cell resolution. 以单细胞分辨率揭示小鼠髓母细胞瘤中由溶瘤病毒驱动的免疫重塑。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-07-19 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.07.006

Jack Hedberg, Adam Studebaker, Luke Smith, Chun-Yu Chen, Jesse J Westfall, Maren Cam, Amy Gross, Ilse Hernandez-Aguirre, Alexia Martin, Doyeon Kim, Ravi Dhital, Yeaseul Kim, Ryan D Roberts, Timothy P Cripe, Elaine R Mardis, Kevin A Cassady, Jeffrey Leonard, Katherine E Miller

{"title":"Oncolytic virus-driven immune remodeling revealed in mouse medulloblastomas at single cell resolution.","authors":"Jack Hedberg, Adam Studebaker, Luke Smith, Chun-Yu Chen, Jesse J Westfall, Maren Cam, Amy Gross, Ilse Hernandez-Aguirre, Alexia Martin, Doyeon Kim, Ravi Dhital, Yeaseul Kim, Ryan D Roberts, Timothy P Cripe, Elaine R Mardis, Kevin A Cassady, Jeffrey Leonard, Katherine E Miller","doi":"10.1016/j.omto.2023.07.006","DOIUrl":"10.1016/j.omto.2023.07.006","url":null,"abstract":"Oncolytic viruses, modified for tumor-restricted infection, are a promising cancer immunotherapeutic, yet much remains to be understood about factors driving their activity and outcome in the tumor microenvironment. Here, we report that oncolytic herpes simplex virus C134, previously found to exert T cell-dependent efficacy in mouse models of glioblastoma, exerts T cell-independent efficacy in mouse models of medulloblastoma, indicating this oncolytic virus uses different mechanisms in different tumors. We investigated C134's behavior in mouse medulloblastomas, using single cell RNA sequencing to map C134-induced gene expression changes across cell types, timepoints, and medulloblastoma subgroup models at whole-transcriptome resolution. Our work details substantial oncolytic virus-induced transcriptional remodeling of medulloblastoma-infiltrating immune cells, 10 subpopulations of monocytes and macrophages collectively demonstrating M1-like responses to C134, and suggests C134 be investigated as a potential new therapy for medulloblastoma.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"39-55"},"PeriodicalIF":5.3,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/29/3f/main.PMC10424001.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10012640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potent and selective eradication of tumor cells by an EpCAM-targeted Ras-degrading enzyme. 一种以 EpCAM 为靶点的 Ras 降解酶能有效并有选择性地消灭肿瘤细胞。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-27 eCollection Date: 2023-09-21 DOI: 10.1016/j.omto.2023.06.002

Valentina Palacio-Castañeda, Bas van de Crommert, Elke Verploegen, Mike Overeem, Jenny van Oostrum, Wouter P R Verdurmen

{"title":"Potent and selective eradication of tumor cells by an EpCAM-targeted Ras-degrading enzyme.","authors":"Valentina Palacio-Castañeda, Bas van de Crommert, Elke Verploegen, Mike Overeem, Jenny van Oostrum, Wouter P R Verdurmen","doi":"10.1016/j.omto.2023.06.002","DOIUrl":"10.1016/j.omto.2023.06.002","url":null,"abstract":"Despite decades of efforts, an urgent need remains to develop tumor cell-selective rat sarcoma (Ras)-targeting therapies that can treat patients with Ras-driven tumors. Here we report modular engineered proteins that degrade Ras selectively in tumor cells that overexpress the tumor cell marker epithelial cell adhesion molecule (EpCAM) by fusing the Ras degrader Ras-Rap1-specific endopeptidase with the translocation domain of the Pseudomonas aeruginosa exotoxin A (ETA) or diphtheria toxin (DT). Redirection to EpCAM is achieved by a designed ankyrin repeat protein. In two-dimensional tumor cell cultures, complete degradation of Ras proteins after 24 h was observed with EpCAM-targeted Ras degraders fused to ETA or DT in EpCAM-overexpressing MCF7 and HCT116 cells, with median inhibition concentration values at sub-nanomolar levels. The viability of EpCAM-low non-cancerous fibroblasts remained unaffected. In a three-dimensional (3D) tumor-on-a-chip system that mimics the natural tumor microenvironment, effective Ras degradation and selective toxicity toward tumor cells, particularly with the ETA-fused constructs, was determined on-chip. To conclude, we demonstrate the potential of modular engineered proteins to kill tumor cells highly selectively by simultaneously exploiting EpCAM as a tumor-specific cell surface molecule as well as Ras as an intracellular oncotarget in a 3D system mimicking the natural tumor microenvironment.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"16-26"},"PeriodicalIF":5.3,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9918953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Radiovirotherapy at twenty. 放射病毒治疗，20岁。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.003

David Dingli

引用次数: 0

PTEN potentiation of oncolytic HSV therapy for glioblastoma. PTEN增强溶瘤性HSV治疗胶质母细胞瘤的作用。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.005

Christian Migliarese, Hiroaki Wakimoto

引用次数: 0

Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response. 靶向白细胞介素-15途径的重组痘苗病毒的溶瘤治疗引发协同反应。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.002

Yasmin Shakiba, Pavel O Vorobyev, Gaukhar M Yusubalieva, Dmitry V Kochetkov, Ksenia V Zajtseva, Marat P Valikhov, Vladimir A Kalsin, Fedor G Zabozlaev, Alevtina S Semkina, Alexander V Troitskiy, Vladimir P Baklaushev, Peter M Chumakov, Anastasia V Lipatova

{"title":"Oncolytic therapy with recombinant vaccinia viruses targeting the interleukin-15 pathway elicits a synergistic response.","authors":"Yasmin Shakiba, Pavel O Vorobyev, Gaukhar M Yusubalieva, Dmitry V Kochetkov, Ksenia V Zajtseva, Marat P Valikhov, Vladimir A Kalsin, Fedor G Zabozlaev, Alevtina S Semkina, Alexander V Troitskiy, Vladimir P Baklaushev, Peter M Chumakov, Anastasia V Lipatova","doi":"10.1016/j.omto.2023.05.002","DOIUrl":"https://doi.org/10.1016/j.omto.2023.05.002","url":null,"abstract":"We developed recombinant variants of oncolytic vaccinia virus LIVP strain expressing interleukin-15 (IL-15) or its receptor subunit alpha (IL-15Rα) to stimulate IL-15-dependent immune cells. We evaluated their oncolytic activity either alone or in combination with each other in vitro and in vivo using the murine CT26 colon carcinoma and 4T1 breast carcinoma models. We demonstrated that the admixture of these recombinant variants could promote the generation of the IL-15/IL-15Rα complex. In vitro studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. In vivo studies showed significant survival benefits and tumor regression in 4T1 breast cancer syngeneic mice that received a combination of LIVP-IL15-RFP with LIVP-IL15Ra-RFP. Histological analysis showed recruited lymphocytes at the tumor region, while no harmful effects to the liver or spleen of the animals were detected. Evaluating tumor-infiltrated lymphocytes represented profound activation of cytotoxic T cells and macrophages in mice receiving combination therapy. Thus, our experiments showed superior oncolytic effectiveness of simultaneous injection of LIVP-IL15-RFP and LIVP-IL15Ra-RFP in breast cancer-bearing mice. The combined therapy by these recombinant variants represents a potent and versatile approach for developing new immunotherapies for breast cancer.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"158-168"},"PeriodicalIF":5.7,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/23/main.PMC10300409.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers. 通过转染嵌合抗原受体或双特异性T细胞接合体的mRNA增强γδ T细胞的有效性。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.007

Scott A Becker, Brian G Petrich, Bing Yu, Kristopher A Knight, Harrison C Brown, Sunil S Raikar, Christopher B Doering, H Trent Spencer

{"title":"Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers.","authors":"Scott A Becker, Brian G Petrich, Bing Yu, Kristopher A Knight, Harrison C Brown, Sunil S Raikar, Christopher B Doering, H Trent Spencer","doi":"10.1016/j.omto.2023.05.007","DOIUrl":"https://doi.org/10.1016/j.omto.2023.05.007","url":null,"abstract":"Adoptive cell therapy (ACT) utilizing γδ T cells is becoming a promising option for the treatment of cancer, because it offers an off-the-shelf allogeneic product that is safe, potent, and clinically effective. Approaches to engineer or enhance immune-competent cells for ACT, like expression of chimeric antigen receptors (CARs) or combination treatments with bispecific T cell engagers, have improved the specificity and cytotoxic potential of ACTs and have shown great promise in preclinical and clinical settings. Here, we test whether electroporation of γδ T cells with CAR or secreted bispecific T cell engager (sBite) mRNA is an effective approach to improve the cytotoxicity of γδ T cells. Using a CD19-specific CAR, approximately 60% of γδ T cells are modified after mRNA electroporation and these cells show potent anticancer activity in vitro and in vivo against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ T cell cytotoxicity, both in vitro and in vivo, and promotes killing of target cells by modified and unmodified γδ T cells. Taken together, we show that transient transfection of γδ T cells with CAR or sBite mRNA by electroporation can be an effective treatment platform as a cancer therapeutic.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"145-157"},"PeriodicalIF":5.7,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ed/97/main.PMC10300408.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9793557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Expanding the landscape of TCR gene therapy targeting MAGE. 拓展靶向MAGE的TCR基因治疗领域。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.004

Zhiyuan Mao, John K Lee

引用次数: 0

Attack of the clones: An NK cell origins story. 克隆的攻击:NK细胞起源的故事。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.02.010

Joseph R Caporale, Dean A Lee

引用次数: 0