Molecular Therapy Oncolytics最新文献_第9页

Controlled release of enhanced cross-hybrid IgGA Fc PD-L1 inhibitors using oncolytic adenoviruses. 利用溶瘤腺病毒控制释放增强型交叉杂交IgGA Fc PD-L1抑制剂。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-03-16 DOI: 10.1016/j.omto.2023.01.006

Firas Hamdan, Michaela Feodoroff, Salvatore Russo, Manlio Fusciello, Sara Feola, Jacopo Chiaro, Gabriella Antignani, Francesca Greco, Jeanette Leusen, Erkko Ylösmäki, Mikaela Grönholm, Vincenzo Cerullo

{"title":"Controlled release of enhanced cross-hybrid IgGA Fc PD-L1 inhibitors using oncolytic adenoviruses.","authors":"Firas Hamdan, Michaela Feodoroff, Salvatore Russo, Manlio Fusciello, Sara Feola, Jacopo Chiaro, Gabriella Antignani, Francesca Greco, Jeanette Leusen, Erkko Ylösmäki, Mikaela Grönholm, Vincenzo Cerullo","doi":"10.1016/j.omto.2023.01.006","DOIUrl":"https://doi.org/10.1016/j.omto.2023.01.006","url":null,"abstract":"Immune checkpoint inhibitors have clinical success in prolonging the life of many cancer patients. However, only a minority of patients benefit from such therapy, calling for further improvements. Currently, most PD-L1 checkpoint inhibitors in the clinic do not elicit Fc effector mechanisms that would substantially increase their efficacy. To gain potency and circumvent off-target effects, we previously designed an oncolytic adenovirus (Ad-Cab) expressing an Fc fusion peptide against PD-L1 on a cross-hybrid immunoglobulin GA (IgGA) Fc. Ad-Cab elicited antibody effector mechanisms of IgG1 and IgA, which led to higher tumor killing compared with each isotype alone and with clinically approved PD-L1 checkpoint inhibitors. In this study, we further improved the therapy to increase the IgG1 Fc effector mechanisms of the IgGA Fc fusion peptide (Ad-Cab FT) by adding four somatic mutations that increase natural killer (NK) cell activation. Ad-Cab FT was shown to work better at lower concentrations compared with Ad-Cab in vitro and in vivo and to have better tumor- and myeloid-derived suppressor cell killing, likely because of higher NK cell activation. Additionally, the biodistribution of the Fc fusion peptide demonstrated targeted release in the tumor microenvironment with minimal or no leakage to the peripheral blood and organs in mice. These data demonstrate effective and safe use of Ad-Cab FT, bidding for further clinical investigation.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"264-276"},"PeriodicalIF":5.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9e/30/main.PMC9995465.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9102590","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

Multi-modal efficacy of a chimeric vesiculovirus expressing the Morreton glycoprotein in sarcoma. 表达莫勒顿糖蛋白的嵌合囊状病毒对肉瘤的多模式疗效。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-03-01 eCollection Date: 2023-06-15 DOI: 10.1016/j.omto.2023.02.009

Chelsae R Watters, Oumar Barro, Natalie M Elliott, Yumei Zhou, Musa Gabere, Elizabeth Raupach, Alexander T Baker, Michael T Barrett, Kenneth H Buetow, Bertram Jacobs, Mahesh Seetharam, Mitesh J Borad, Bolni Marius Nagalo

{"title":"Multi-modal efficacy of a chimeric vesiculovirus expressing the Morreton glycoprotein in sarcoma.","authors":"Chelsae R Watters, Oumar Barro, Natalie M Elliott, Yumei Zhou, Musa Gabere, Elizabeth Raupach, Alexander T Baker, Michael T Barrett, Kenneth H Buetow, Bertram Jacobs, Mahesh Seetharam, Mitesh J Borad, Bolni Marius Nagalo","doi":"10.1016/j.omto.2023.02.009","DOIUrl":"10.1016/j.omto.2023.02.009","url":null,"abstract":"Vesiculoviruses are attractive oncolytic virus platforms due to their rapid replication, appreciable transgene capacity, broad tropism, limited preexisting immunity, and tumor selectivity through type I interferon response defects in malignant cells. We developed a synthetic chimeric virus (VMG) expressing the glycoprotein (G) from Morreton virus (MorV) and utilizing the remaining structural genes from vesicular stomatitis virus (VSV). VMG exhibited in vitro efficacy by inducing oncolysis in a broad range of sarcoma subtypes across multiple species. Notably, all cell lines tested showed the ability of VMG to yield productive infection with rapid replication kinetics and induction of apoptosis. Furthermore, pilot safety evaluations of VMG in immunocompetent, non-tumor-bearing mice showed an absence of toxicity with intranasal doses as high as 1e10 50% tissue culture infectious dose (TCID50)/kg. Locoregional administration of VMG in vivo resulted in tumor reduction in an immunodeficient Ewing sarcoma xenograft at doses as low as 2e5 TCID50. In a murine syngeneic fibrosarcoma model, while no tumor inhibition was achieved with VMG, there was a robust induction of CD8+ T cells within the tumor. The studies described herein establish the promising potential for VMG to be used as a novel oncolytic virotherapy platform with anticancer effects in sarcoma.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"29 ","pages":"4-14"},"PeriodicalIF":5.7,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/71/f4/main.PMC10033453.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9245945","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

Multivalent in vivo delivery of DNA-encoded bispecific T cell engagers effectively controls heterogeneous GBM tumors and mitigates immune escape. DNA 编码的双特异性 T 细胞吞噬因子的多价体内递送可有效控制异质性 GBM 肿瘤并减轻免疫逃逸。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-02-16 eCollection Date: 2023-03-16 DOI: 10.1016/j.omto.2023.02.004

Daniel H Park, Kevin Liaw, Pratik Bhojnagarwala, Xizhou Zhu, Jihae Choi, Ali R Ali, Devivasha Bordoloi, Ebony N Gary, Ryan P O'Connell, Abhijeet Kulkarni, Diana Guimet, Trevor Smith, Alfredo Perales-Puchalt, Ami Patel, David B Weiner

{"title":"Multivalent in vivo delivery of DNA-encoded bispecific T cell engagers effectively controls heterogeneous GBM tumors and mitigates immune escape.","authors":"Daniel H Park, Kevin Liaw, Pratik Bhojnagarwala, Xizhou Zhu, Jihae Choi, Ali R Ali, Devivasha Bordoloi, Ebony N Gary, Ryan P O'Connell, Abhijeet Kulkarni, Diana Guimet, Trevor Smith, Alfredo Perales-Puchalt, Ami Patel, David B Weiner","doi":"10.1016/j.omto.2023.02.004","DOIUrl":"10.1016/j.omto.2023.02.004","url":null,"abstract":"Glioblastoma multiforme (GBM) is among the most difficult cancers to treat with a 5-year survival rate less than 5%. An immunotherapeutic vaccine approach targeting GBM-specific antigen, EGFRvIII, previously demonstrated important clinical impact. However, immune escape variants were reported in the trial, suggesting that multivalent approaches targeting GBM-associated antigens may be of importance. Here we focused on multivalent in vivo delivery of synthetic DNA-encoded bispecific T cell engagers (DBTEs) targeting two GBM-associated antigens, EGFRvIII and HER2. We designed and optimized an EGFRvIII-DBTE that induced T cell-mediated cytotoxicity against EGFRvIII-expressing tumor cells. In vivo delivery in a single administration of EGFRvIII-DBTE resulted in durable expression over several months in NSG mice and potent tumor control and clearance in both peripheral and orthotopic animal models of GBM. Next, we combined delivery of EGFRvIII-DBTEs with an HER2-targeting DBTE to treat heterogeneous GBM tumors. In vivo delivery of dual DBTEs targeting these two GBM-associated antigens exhibited enhanced tumor control and clearance in a heterogeneous orthotopic GBM challenge, while treatment with single-target DBTE ultimately allowed for tumor escape. These studies support that combined delivery of DBTEs, targeting both EGFRvIII and HER2, can potentially improve outcomes of GBM immunotherapy, and such multivalent approaches deserve additional study.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"249-263"},"PeriodicalIF":5.7,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10006507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9114261","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

Reprogramming the tumor microenvironment leverages CD8⁺ T cell responses to a shared tumor/self antigen in ovarian cancer. 重编程肿瘤微环境可利用 CD8+ T 细胞对卵巢癌中肿瘤/自身共同抗原的反应。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-02-09 eCollection Date: 2023-03-16 DOI: 10.1016/j.omto.2023.02.002

Anna Mistarz, Marta Winkler, Sebastiano Battaglia, Song Liu, Alan Hutson, Hanna Rokita, Andrea Gambotto, Kunle O Odunsi, Prashant K Singh, A J Robert McGray, Jianmin Wang, Danuta Kozbor

{"title":"Reprogramming the tumor microenvironment leverages CD8+ T cell responses to a shared tumor/self antigen in ovarian cancer.","authors":"Anna Mistarz, Marta Winkler, Sebastiano Battaglia, Song Liu, Alan Hutson, Hanna Rokita, Andrea Gambotto, Kunle O Odunsi, Prashant K Singh, A J Robert McGray, Jianmin Wang, Danuta Kozbor","doi":"10.1016/j.omto.2023.02.002","DOIUrl":"10.1016/j.omto.2023.02.002","url":null,"abstract":"Tumor antigen-driven responses to weakly immunogenic self-antigens and neoantigens directly affect treatment efficacy following immunotherapy. Using orthotopically grown SV40 T antigen+ ovarian carcinoma in antigen-naive wild-type or TgMISIIR-TAg-Low transgenic mice expressing SV40 T antigen as a self-antigen, we investigated the impact of CXCR4-antagonist-armed oncolytic virotherapy on tumor progression and antitumor immunity. Immunostaining and single-cell RNA sequencing analyses of the peritoneal tumor microenvironment of untreated tumors in syngeneic wild-type mice revealed the presence of SV40 T antigen-specific CD8+ T cells, a balanced M1/M2 transcriptomic signature of tumor-associated macrophages, and immunostimulatory cancer-associated fibroblasts. This contrasted with polarized M2 tumor-associated macrophages, immunosuppressive cancer-associated fibroblasts, and poor immune activation in TgMISIIR-TAg-Low mice. Intraperitoneal delivery of CXCR4-antagonist-armed oncolytic vaccinia virus led to nearly complete depletion of cancer-associated fibroblasts, M1 polarization of macrophages, and generation of SV40 T antigen-specific CD8+ T cells in transgenic mice. Cell depletion studies revealed that the therapeutic effect of armed oncolytic virotherapy was dependent primarily on CD8+ cells. These results demonstrate that targeting the interaction between immunosuppressive cancer-associated fibroblasts and macrophages in the tolerogenic tumor microenvironment by CXCR4-A-armed oncolytic virotherapy induces tumor/self-specific CD8+ T cell responses and consequently increases therapeutic efficacy in an immunocompetent ovarian cancer model.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"230-248"},"PeriodicalIF":5.7,"publicationDate":"2023-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9982455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9759551","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

esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation. 表达 esRAGE 的 oHSV 可通过抑制内皮细胞活化提高抗肿瘤疗效。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2023-01-16 eCollection Date: 2023-03-16 DOI: 10.1016/j.omto.2023.01.003

Jessica Swanner, Ji Seon Shim, Kimberly A Rivera-Caraballo, Karina Vázquez-Arreguín, Bangxing Hong, Alberto J Bueso-Perez, Tae Jin Lee, Yeshavanth Kumar Banasavadi-Siddegowda, Balveen Kaur, Ji Young Yoo

{"title":"esRAGE-expressing oHSV enhances anti-tumor efficacy by inhibition of endothelial cell activation.","authors":"Jessica Swanner, Ji Seon Shim, Kimberly A Rivera-Caraballo, Karina Vázquez-Arreguín, Bangxing Hong, Alberto J Bueso-Perez, Tae Jin Lee, Yeshavanth Kumar Banasavadi-Siddegowda, Balveen Kaur, Ji Young Yoo","doi":"10.1016/j.omto.2023.01.003","DOIUrl":"10.1016/j.omto.2023.01.003","url":null,"abstract":"High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule that plays an important role in inflammation and tumorigenesis. Receptor for advanced glycation end products (RAGE) is one of the major receptors to which extracellular HMGB1 binds to mediate its activity. RAGE is highly expressed on the endothelial cells (ECs) and regulates endothelial permeability during inflammation. Here, we introduced the endogenous secretory form of RAGE (esRAGE) as a decoy receptor for RAGE ligands into an oncolytic herpes simplex virus 1 (oHSV) (OVesRAGE), which, upon release, can function to block RAGE signaling. OVesRAGE significantly decreased phosphorylation of MEK1/2 and Erk and increased cleaved PARP in glioblastoma (GBM) cells in vitro and in vivo. oHSV-infected GBM cells co-cultured with ECs were used to test OVesRAGE effect on EC activation, vessel leakiness, virus replication, and tumor cell killing. OVesRAGE could effectively secrete esRAGE and rescue virus-induced EC migration and activation. Reduced EC activation facilitated virus replication in tumor cells when co-cultured with ECs. Finally, OVesRAGE significantly enhanced therapeutic efficacy in GBM-bearing mice. Collectively, our data demonstrate that HMGB1-RAGE signaling could be a promising target and that its inhibition is a feasible approach to improve the efficacy of oHSV therapy.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"171-181"},"PeriodicalIF":5.7,"publicationDate":"2023-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9918391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9203029","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

Expanded NK cells used for adoptive cell therapy maintain diverse clonality and contain long-lived memory-like NK cell populations. 用于采用细胞疗法的扩增 NK 细胞可保持不同的克隆性，并含有长效记忆型 NK 细胞群。

IF 5.3 2区医学

Molecular Therapy Oncolytics Pub Date : 2022-12-27 eCollection Date: 2023-03-16 DOI: 10.1016/j.omto.2022.12.006

David S J Allan, Chuanfeng Wu, Ryland D Mortlock, Mala Chakraborty, Katayoun Rezvani, Jan K Davidson-Moncada, Cynthia E Dunbar, Richard W Childs

{"title":"Expanded NK cells used for adoptive cell therapy maintain diverse clonality and contain long-lived memory-like NK cell populations.","authors":"David S J Allan, Chuanfeng Wu, Ryland D Mortlock, Mala Chakraborty, Katayoun Rezvani, Jan K Davidson-Moncada, Cynthia E Dunbar, Richard W Childs","doi":"10.1016/j.omto.2022.12.006","DOIUrl":"10.1016/j.omto.2022.12.006","url":null,"abstract":"Multiple clinical trials exploring the potential of adoptive natural killer (NK) cell therapy for cancer have employed ex vivo expansion using feeder cells to obtain large numbers of NK cells. We have previously utilized the rhesus macaque model to clonally track the NK cell progeny of barcode-transduced CD34+ stem and progenitor cells after transplant. In this study, NK cells from barcoded rhesus macaques were used to study the changes in NK cell clonal patterns that occurred during ex vivo expansion using culture protocols similar to those employed in clinical preparation of human NK cells including irradiated lymphoblastoid cell line (LCL) feeder cells or K562 cells expressing 4-1BBL and membrane-bound interleukin-21 (IL-21). NK expansion cultures resulted in the proliferation of clonally diverse NK cells, which, at day 14 harvest, contained greater than 50% of the starting barcode repertoire. Diversity as measured by Shannon index was maintained after culture. With both LCL and K562 feeders, proliferation of long-lived putative memory-like NK cell clones was observed, with these clones continuing to constitute a mean of 31% of the total repertoire of expanded cells. These experiments provide insight into the clonal makeup of expanded NK cell clinical products.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"74-87"},"PeriodicalIF":5.3,"publicationDate":"2022-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/50/57/main.PMC9842935.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9178064","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

Development and comparison of ⁶⁸Ga/¹⁸F/⁶⁴Cu-labeled nanobody tracers probing Claudin18.2. 探测claud18.2的68Ga/18F/ 64cu标记纳米体示踪剂的研制与比较

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2022-12-15 DOI: 10.1016/j.omto.2022.11.003

Weijun Wei, Di Zhang, You Zhang, Lianghua Li, Yuchen Jin, Shuxian An, Chun Lv, Haitao Zhao, Cheng Wang, Yanshan Huang, Jiali Dong, Gang Huang, Jianjun Liu

{"title":"Development and comparison of 68Ga/18F/64Cu-labeled nanobody tracers probing Claudin18.2.","authors":"Weijun Wei, Di Zhang, You Zhang, Lianghua Li, Yuchen Jin, Shuxian An, Chun Lv, Haitao Zhao, Cheng Wang, Yanshan Huang, Jiali Dong, Gang Huang, Jianjun Liu","doi":"10.1016/j.omto.2022.11.003","DOIUrl":"https://doi.org/10.1016/j.omto.2022.11.003","url":null,"abstract":"Claudin 18.2 (CLDN18.2) is an emerging target for the treatment of gastric cancers. We aim to develop tracers to image the expression of CLDN18.2. A humanized nanobody targeting CLDN18.2 (clone hu19V3) was produced and labeled with 68Ga, 64Cu, and 18F. The tracers were investigated in subcutaneous and metastatic models established using two different mouse types (nude and Balb/c mice) and two different cell lines (CHO-CLDN18.2 and CT26-CLDN18.2). Gastric cancer patient-derived xenograft (PDX) models were further established for validation experiments. Three novel CLDN18.2-targeted tracers (i.e., [68Ga]Ga-NOTA-hu19V3, [64Cu]Cu-NOTA-hu19V3, and [18F]F-hu19V3) were developed with good radiochemical yields and excellent radiochemical purities. [68Ga]Ga-NOTA-hu19V3 immuno-positron emission tomography (immunoPET) rapidly delineated subcutaneous CHO-CLDN18.2 lesions and CT26-CLDN18.2 tumors, as well as showing excellent diagnostic value in PDX models naturally expressing CLDN18.2. While [68Ga]Ga-NOTA-hu19V3 had high kidney accumulation, [64Cu]Cu-NOTA-hu19V3 showed reduced kidney accumulation and improved image contrast at late time points. Moreover, [18F]F-hu19V3 was developed via click chemistry reaction under mild conditions and precisely disseminated CHO-CLDN18.2 lesions in the lungs. Furthermore, region of interest analysis, biodistribution study, and histopathological staining results correlated well with the in vivo imaging results. Taken together, immunoPET imaging with the three tracers can reliably visualize CLDN18.2 expression.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"27 ","pages":"305-314"},"PeriodicalIF":5.7,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1a/51/main.PMC9747674.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10497609","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: 5

Oncolytic Urabe mumps virus: A promising virotherapy for triple-negative breast cancer. 溶瘤性乌拉伯腮腺炎病毒:一种有前途的三阴性乳腺癌病毒疗法。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2022-12-15 DOI: 10.1016/j.omto.2022.11.002

Marshall D Behrens, Robert J Stiles, Gennett M Pike, Laura A Sikkink, Yongxian Zhuang, Jia Yu, Liewei Wang, Judy C Boughey, Matthew P Goetz, Mark J Federspiel

{"title":"Oncolytic Urabe mumps virus: A promising virotherapy for triple-negative breast cancer.","authors":"Marshall D Behrens, Robert J Stiles, Gennett M Pike, Laura A Sikkink, Yongxian Zhuang, Jia Yu, Liewei Wang, Judy C Boughey, Matthew P Goetz, Mark J Federspiel","doi":"10.1016/j.omto.2022.11.002","DOIUrl":"https://doi.org/10.1016/j.omto.2022.11.002","url":null,"abstract":"Historically, the clinical utility of oncolytic virotherapy as a treatment for a wide range of cancer types was first demonstrated by three pilot human clinical trials conducted in Japan in the 1970s and 1980s using a wild-type Urabe mumps virus (MuV) clinical isolate. Using a sample of the actual original oncolytic Urabe MuV clinical trial virus stock (MuV-U-Japan) used in these Japanese clinical trials, we found that MuV-U-Japan consisted of a wide variety of very closely related Urabe MuVs that differed by an average of only three amino acids. Two MuV-U-Japan isolates, MuV-UA and MuV-UC, potently killed a panel of established human breast cancer cell lines in vitro, significantly extended survival of nude mice with human triple-negative breast cancer (TNBC) MDA-MB-231 tumor xenografts in vivo, and demonstrated significant killing activity against breast cancer patient-derived xenograft (PDX) cell lines grown as 3D organoids, including PDXs from patients resistant to anthracycline- and taxane-based chemotherapy. We also report success in developing a large-scale MuV-U production and purification process suitable for supporting Investigational New Drug applications for clinical trials. This study demonstrates the suitability of the MuV-UC virus for translation to modern clinical trials for treating patients with TNBC.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"27 ","pages":"239-255"},"PeriodicalIF":5.7,"publicationDate":"2022-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/95/main.PMC9703006.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10702301","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

A library of cancer testis specific T cell receptors for T cell receptor gene therapy. 癌症睾丸特异性T细胞受体库，用于T细胞受体基因治疗。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2022-12-02 eCollection Date: 2023-03-16 DOI: 10.1016/j.omto.2022.11.007

Marije A J de Rooij, Dennis F G Remst, Dirk M van der Steen, Anne K Wouters, Renate S Hagedoorn, Michel G D Kester, Miranda H Meeuwsen, Tassilo L A Wachsmann, Arnoud H de Ru, Peter A van Veelen, Els M E Verdegaal, J H Frederik Falkenburg, Mirjam H M Heemskerk

{"title":"A library of cancer testis specific T cell receptors for T cell receptor gene therapy.","authors":"Marije A J de Rooij, Dennis F G Remst, Dirk M van der Steen, Anne K Wouters, Renate S Hagedoorn, Michel G D Kester, Miranda H Meeuwsen, Tassilo L A Wachsmann, Arnoud H de Ru, Peter A van Veelen, Els M E Verdegaal, J H Frederik Falkenburg, Mirjam H M Heemskerk","doi":"10.1016/j.omto.2022.11.007","DOIUrl":"10.1016/j.omto.2022.11.007","url":null,"abstract":"To increase the number of cancer patients that can be treated with T cell receptor (TCR) gene therapy, we aimed to identify a set of high-affinity cancer-specific TCRs targeting different melanoma-associated antigens (MAGEs). In this study, peptides derived from MAGE genes with tumor-specific expression pattern were identified by human leukocyte antigen (HLA) peptidomics. Next, peptide-HLA tetramers were generated, and used to sort MAGE-specific CD8+ T cell clones from the allogeneic (allo) HLA repertoire of healthy donors. To evaluate the clinical potential, most potent TCRs were sequenced, transferred into peripheral blood-derived CD8+ T cells, and tested for antitumor efficacy. In total we identified, seven MAGE-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6, and MAGE-A9 in the context of HLA-A∗01:01, -A∗02:01, -A∗03:01, -B∗07:02, -B∗35:01, or -C∗07:02. TCR gene transfer into CD8⁺ T cells resulted in efficient reactivity against a variety of different tumor types, while no cross-reactivity was detected. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells were observed in the orthotopic xenograft model for established multiple myeloma. The identification of seven MAGE-specific TCRs expands the pool of cancer patients eligible for TCR gene therapy and increases possibilities for personalized TCR gene therapy.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"1-14"},"PeriodicalIF":5.7,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9792401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10833445","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

Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model. 在小鼠多发性骨髓瘤模型中，微RNA靶向溶瘤孟病毒的多胞苷道缺失优化了治疗指数。

IF 5.7 2区医学

Molecular Therapy Oncolytics Pub Date : 2022-12-02 eCollection Date: 2023-03-16 DOI: 10.1016/j.omto.2022.11.006

Velia Penza, Justin W Maroun, Rebecca A Nace, Autumn J Schulze, Stephen J Russell

{"title":"Polycytidine tract deletion from microRNA-detargeted oncolytic Mengovirus optimizes the therapeutic index in a murine multiple myeloma model.","authors":"Velia Penza, Justin W Maroun, Rebecca A Nace, Autumn J Schulze, Stephen J Russell","doi":"10.1016/j.omto.2022.11.006","DOIUrl":"10.1016/j.omto.2022.11.006","url":null,"abstract":"Mengovirus is an oncolytic picornavirus whose broad host range allows for testing in immunocompetent cancer models. Two pathogenicity-ablating approaches, polycytidine (polyC) tract truncation and microRNA (miRNA) targets insertion, eliminated the risk of encephalomyocarditis. To investigate whether a polyC truncated, miRNA-detargeted oncolytic Mengovirus might be boosted, we partially or fully rebuilt the polyC tract into the 5' noncoding region (NCR) of polyC-deleted (MC0) oncolytic constructs (NC) carrying miRNA target (miRT) insertions to eliminate cardiac/muscular (miR-133b and miR-208a) and neuronal (miR-124) tropisms. PolyC-reconstituted viruses (MC24-NC and MC37-NC) replicated in vitro and showed the expected tropism restrictions, but reduced cytotoxicity and miRT deletions were frequently observed. In the MPC-11 immune competent mouse plasmacytoma model, both intratumoral and systemic administration of MC0-NC led to faster tumor responses than MC24-NC or MC37-NC, with combined durable complete response rates of 75%, 0.5%, and 30%, respectively. Secondary viremia was higher following MC0-NC versus MC24-NC or MC37-NC therapy. Sequence analysis of virus progeny from treated mice revealed a high prevalence of miRT sequences loss among MC24- and MC37- viral genomes, but not in MC0-NC. Overall, MC0-NC was capable of stably retaining miRT sites and provided a more effective treatment and is therefore our lead Mengovirus candidate for clinical translation.","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"28 ","pages":"15-30"},"PeriodicalIF":5.7,"publicationDate":"2022-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7a/f2/main.PMC9800256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10513363","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