Molecular Therapy Oncolytics最新文献_第6页

Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor. 基于工程下游转录因子的CD19 CAR-T细胞活化调控。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.005

Duško Lainšček, Anja Golob-Urbanc, Veronika Mikolič, Jelica Pantović-Žalig, Špela Malenšek, Roman Jerala

{"title":"Regulation of CD19 CAR-T cell activation based on an engineered downstream transcription factor.","authors":"Duško Lainšček, Anja Golob-Urbanc, Veronika Mikolič, Jelica Pantović-Žalig, Špela Malenšek, Roman Jerala","doi":"10.1016/j.omto.2023.04.005","DOIUrl":"https://doi.org/10.1016/j.omto.2023.04.005","url":null,"abstract":"CAR-T cells present a highly effective therapeutic option for several malignant diseases, based on their ability to recognize the selected tumor surface marker in an MHC-independent manner. This triggers cell activation and cytokine production, resulting in the killing of the cancerous cell presenting markers recognized by the chimeric antigen receptor. CAR-T cells are highly potent serial killers that may cause serious side effects, so their activity needs to be carefully controlled. Here we designed a system to control the proliferation and activation state of CARs based on downstream NFAT transcription factors, whose activity can be regulated via chemically induced heterodimerization systems. Chemical regulators were used to either transiently trigger engineered T cell proliferation or suppress CAR-mediated activation when desired or to enhance activation of CAR-T cells upon engagement of cancer cells, shown also in vivo. Additionally, an efficient sensor to monitor activated CD19 CAR-T cells in vivo was introduced. This implementation in CAR-T cell regulation offers an efficient way for on-demand external control of CAR-T cell activity to improve their safety.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"77-90"},"PeriodicalIF":5.7,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9516656","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

Adenovirotherapy delivering cross-hybrid IgGA Fc engineering PD-L1 inhibitors for enhanced cancer immunotherapy. 腺病毒疗法提供交叉杂交IgGA Fc工程PD-L1抑制剂，用于增强癌症免疫治疗。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.05.001

Guo Zhao, Shuhang Wang, Ning Li

引用次数: 0

Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells. 柯萨奇病毒A21对耐药肿瘤B细胞的疗效。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.03.002

Matthew Holmes, Gina B Scott, Samuel Heaton, Tyler Barr, Basem Askar, Louise M E Müller, Victoria A Jennings, Christy Ralph, Cathy Burton, Alan Melcher, Peter Hillmen, Christopher Parrish, Fiona Errington-Mais

{"title":"Efficacy of coxsackievirus A21 against drug-resistant neoplastic B cells.","authors":"Matthew Holmes, Gina B Scott, Samuel Heaton, Tyler Barr, Basem Askar, Louise M E Müller, Victoria A Jennings, Christy Ralph, Cathy Burton, Alan Melcher, Peter Hillmen, Christopher Parrish, Fiona Errington-Mais","doi":"10.1016/j.omto.2023.03.002","DOIUrl":"https://doi.org/10.1016/j.omto.2023.03.002","url":null,"abstract":"Primary drug resistance and minimal residual disease are major challenges in the treatment of B cell neoplasms. Therefore, this study aimed to identify a novel treatment capable of eradicating malignant B cells and drug-resistant disease. Oncolytic viruses eradicate malignant cells by direct oncolysis and activation of anti-tumor immunity, have proven anti-cancer efficacy, and are safe and well tolerated in clinical use. Here, we demonstrate that the oncolytic virus coxsackievirus A21 can kill a range of B cell neoplasms, irrespective of an anti-viral interferon response. Moreover, CVA21 retained its capacity to kill drug-resistant B cell neoplasms, where drug resistance was induced by co-culture with tumor microenvironment support. In some cases, CVA21 efficacy was actually enhanced, in accordance with increased expression of the viral entry receptor ICAM-1. Importantly, the data confirmed preferential killing of malignant B cells and CVA21 dependence on oncogenic B cell signaling pathways. Significantly, CVA21 also activated natural killer (NK) cells to kill neoplastic B cells and drug-resistant B cells remained susceptible to NK cell-mediated lysis. Overall, these data reveal a dual mode of action of CVA21 against drug-resistant B cells and support the development of CVA21 for the treatment of B cell neoplasms.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"17-29"},"PeriodicalIF":5.7,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10106520/pdf/main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9389951","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

Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis. 牛痘病毒与肽受体放射治疗协同提高腹膜癌的治疗效果。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.001

Kathryn Ottolino-Perry, David Mealiea, Clara Sellers, Sergio A Acuna, Fernando A Angarita, Lili Okamoto, Deborah Scollard, Mihaela Ginj, Raymond Reilly, J Andrea McCart

{"title":"Vaccinia virus and peptide-receptor radiotherapy synergize to improve treatment of peritoneal carcinomatosis.","authors":"Kathryn Ottolino-Perry, David Mealiea, Clara Sellers, Sergio A Acuna, Fernando A Angarita, Lili Okamoto, Deborah Scollard, Mihaela Ginj, Raymond Reilly, J Andrea McCart","doi":"10.1016/j.omto.2023.04.001","DOIUrl":"https://doi.org/10.1016/j.omto.2023.04.001","url":null,"abstract":"Tumor-specific overexpression of receptors enables a variety of targeted cancer therapies, exemplified by peptide-receptor radiotherapy (PRRT) for somatostatin receptor (SSTR)-positive neuroendocrine tumors. While effective, PRRT is restricted to tumors with SSTR overexpression. To overcome this limitation, we propose using oncolytic vaccinia virus (vvDD)-mediated receptor gene transfer to permit molecular imaging and PRRT in tumors without endogenous SSTR overexpression, a strategy termed radiovirotherapy. We hypothesized that vvDD-SSTR combined with a radiolabeled somatostatin analog could be deployed as radiovirotherapy in a colorectal cancer peritoneal carcinomatosis model, producing tumor-specific radiopeptide accumulation. Following vvDD-SSTR and 177Lu-DOTATOC treatment, viral replication and cytotoxicity, as well as biodistribution, tumor uptake, and survival, were evaluated. Radiovirotherapy did not alter virus replication or biodistribution, but synergistically improved vvDD-SSTR-induced cell killing in a receptor-dependent manner and significantly increased the tumor-specific accumulation and tumor-to-blood ratio of 177Lu-DOTATOC, making tumors imageable by microSPECT/CT and causing no significant toxicity. 177Lu-DOTATOC significantly improved survival over virus alone when combined with vvDD-SSTR but not control virus. We have therefore demonstrated that vvDD-SSTR can convert receptor-negative tumors into receptor-positive tumors and facilitate molecular imaging and PRRT using radiolabeled somatostatin analogs. Radiovirotherapy represents a promising treatment strategy with potential applications in a wide range of cancers.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"44-58"},"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/3f/a9/main.PMC10173076.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9838467","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

Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T. 持久缓解与R/R B-ALL的CAR-T持久性和初始CAR-T的长期持久性有关。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.003

Li Shiqi, Zhang Jiasi, Chen Lvzhe, Xu Huailong, He Liping, Liu Lin, Zhang Qianzhen, Yuan Zhongtao, Shen Junjie, Chen Zucong, Zhang Yingzi, Wang Meiling, Li Yunyan, Wang Linling, Fang Lihua, Chen Yingnian, Zhu Wei, Li Yu, Luo Le, Wang Youcheng, Zhang Dingsong, Dong Yancheng, Yin Ping, Zhang Lihua, Li Xiaoping, Hu Xiaozhuang, Zheng Zhongzheng, Yang Zhi, Qian Cheng, Wang Sanbin

{"title":"Durable remission related to CAR-T persistence in R/R B-ALL and long-term persistence potential of prime CAR-T.","authors":"Li Shiqi, Zhang Jiasi, Chen Lvzhe, Xu Huailong, He Liping, Liu Lin, Zhang Qianzhen, Yuan Zhongtao, Shen Junjie, Chen Zucong, Zhang Yingzi, Wang Meiling, Li Yunyan, Wang Linling, Fang Lihua, Chen Yingnian, Zhu Wei, Li Yu, Luo Le, Wang Youcheng, Zhang Dingsong, Dong Yancheng, Yin Ping, Zhang Lihua, Li Xiaoping, Hu Xiaozhuang, Zheng Zhongzheng, Yang Zhi, Qian Cheng, Wang Sanbin","doi":"10.1016/j.omto.2023.04.003","DOIUrl":"https://doi.org/10.1016/j.omto.2023.04.003","url":null,"abstract":"CD19-targeted chimeric antigen receptor T lymphocytes (CAR-T) has demonstrated a high proportion of complete remission in the treatment of relapsed refractory acute B cell lymphoblastic leukemia (r/r B-ALL). It is of great clinical significance to explore which factors will impact long-term disease-free survival of patients with r/r B-ALL after CAR-T therapy without bridging bone marrow transplantation. Our study found that, in patients with r/r B-ALL without bridging transplantation, the patients' age; infusion dosage; whether they had undergone allo-stem cell transplantation before CAR-T therapy, using CD-19-targeted or CD19/CD22-dual-targeted CAR-T; whether there is fusion gene; tumor burden before therapy; and comorbidity had no significant relationship with their long-term disease-free survival. We found only that CAR-T persistence was highly correlated with patients' long-term disease-free survival. So, we further profiled CAR-T cells using single-cell sequencing and found that there is a specific T cell subset that may be associated with the long-term persistence of CAR-T. Finally, according to the single-cell sequencing results, we established cell production process named PrimeCAR, which shared common signaling pathways with the T cell subset identified. In the preliminary clinical study, prime CAR-Ts yield good persistence in peripheral blood of patients with B-ALL and lymphoma, without observing grade 2 or higher cytokine release syndrome.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"107-117"},"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/7a/13/main.PMC10196916.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9503867","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

Opportunities and challenges of combining adoptive cellular therapy with oncolytic virotherapy. 过继细胞治疗与溶瘤病毒治疗相结合的机遇与挑战。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.008

Joseph A Mamola, Chun-Yu Chen, Mark A Currier, Kevin Cassady, Dean A Lee, Timothy P Cripe

引用次数: 1

Triple combination therapy for pancreatic cancer remodels stroma and improves survival. 三联疗法治疗胰腺癌重塑基质，提高生存率。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.03.001

Karina Vázquez-Arreguín, Balveen Kaur

引用次数: 0

New insights and options into the mechanisms and effects of combined targeted therapy and immunotherapy in prostate cancer. 前列腺癌联合靶向治疗和免疫治疗的机制和效果的新见解和选择。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.007

Mingen Lin, Xue Sun, Lei Lv

{"title":"New insights and options into the mechanisms and effects of combined targeted therapy and immunotherapy in prostate cancer.","authors":"Mingen Lin, Xue Sun, Lei Lv","doi":"10.1016/j.omto.2023.04.007","DOIUrl":"https://doi.org/10.1016/j.omto.2023.04.007","url":null,"abstract":"Chronic inflammation is believed to drive prostate carcinogenesis by producing reactive oxygen species or reactive nitrogen species to induce DNA damage. This effect might subsequently cause epigenetic and genomic alterations, leading to malignant transformation. Although established therapeutic advances have extended overall survival, tumors in patients with advanced prostate cancer are prone to metastasis, transformation into metastatic castration-resistant prostate cancer, and therapeutic resistance. The tumor microenvironment (TME) of prostate cancer is involved in carcinogenesis, invasion and drug resistance. A plethora of preclinical studies have focused on immune-based therapies. Understanding the intricate TME system in prostate cancer may hold much promise for developing novel therapies, designing combinational therapeutic strategies, and further overcoming resistance to established treatments to improve the lives of prostate cancer patients. In this review, we discuss nonimmune components and various immune cells within the TME and their putative roles during prostate cancer initiation, progression, and metastasis. We also outline the updated fundamental research focusing on therapeutic advances of targeted therapy as well as combinational options for prostate cancer.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"91-106"},"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/d5/b0/main.PMC10199166.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9509114","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: 4

Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity. 携带细菌GBP1降解物的溶瘤性单纯疱疹病毒提高了抗肿瘤活性。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-06-15 DOI: 10.1016/j.omto.2023.04.006

Jun Xie, Shaowei Wang, Yunhong Zhong, Ming Gao, Xuezhang Tian, Liting Zhang, Dongli Pan, Qingsong Qin, Bing Wu, Ke Lan, Zhi-Jun Sun, Junjie Zhang

{"title":"Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.","authors":"Jun Xie, Shaowei Wang, Yunhong Zhong, Ming Gao, Xuezhang Tian, Liting Zhang, Dongli Pan, Qingsong Qin, Bing Wu, Ke Lan, Zhi-Jun Sun, Junjie Zhang","doi":"10.1016/j.omto.2023.04.006","DOIUrl":"https://doi.org/10.1016/j.omto.2023.04.006","url":null,"abstract":"Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"61-76"},"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/0b/1f/main.PMC10200819.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9516659","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

Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses. 使用顺序原发性和肿瘤逃逸选择性溶瘤病毒的陷阱和伏击疗法。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-05-22 eCollection Date: 2023-06-15 DOI: 10.1016/j.omto.2023.05.006

Mason J Webb, Timothy Kottke, Benjamin L Kendall, Jack Swanson, Chisom Uzendu, Jason Tonne, Jill Thompson, Muriel Metko, Madelyn Moore, Mitesh Borad, Lewis Roberts, Rosa M Diaz, Michael Olin, Antonella Borgatti, Richard Vile

{"title":"Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses.","authors":"Mason J Webb, Timothy Kottke, Benjamin L Kendall, Jack Swanson, Chisom Uzendu, Jason Tonne, Jill Thompson, Muriel Metko, Madelyn Moore, Mitesh Borad, Lewis Roberts, Rosa M Diaz, Michael Olin, Antonella Borgatti, Richard Vile","doi":"10.1016/j.omto.2023.05.006","DOIUrl":"10.1016/j.omto.2023.05.006","url":null,"abstract":"In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-β induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-β oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"129-142"},"PeriodicalIF":5.3,"publicationDate":"2023-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/35/43/main.PMC10258242.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9633097","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