Carolin Kitzberger, Khuram Shehzad, Volker Morath, Rebekka Spellerberg, Julius Ranke, Katja Steiger, Roland E Kälin, Gabriele Multhoff, Matthias Eiber, Franz Schilling, Rainer Glass, Wolfgang A Weber, Ernst Wagner, Peter J Nelson, Christine Spitzweg
{"title":"Interleukin-6-controlled, mesenchymal stem cell-based sodium/iodide symporter gene therapy improves survival of glioblastoma-bearing mice.","authors":"Carolin Kitzberger, Khuram Shehzad, Volker Morath, Rebekka Spellerberg, Julius Ranke, Katja Steiger, Roland E Kälin, Gabriele Multhoff, Matthias Eiber, Franz Schilling, Rainer Glass, Wolfgang A Weber, Ernst Wagner, Peter J Nelson, Christine Spitzweg","doi":"10.1016/j.omto.2023.08.004","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.004","url":null,"abstract":"<p><p>New treatment strategies are urgently needed for glioblastoma (GBM)-a tumor resistant to standard-of-care treatment with a high risk of recurrence and extremely poor prognosis. Based on their intrinsic tumor tropism, adoptively applied mesenchymal stem cells (MSCs) can be harnessed to deliver the theranostic sodium/iodide symporter (<i>NIS</i>) deep into the tumor microenvironment. Interleukin-6 (IL-6) is a multifunctional, highly expressed cytokine in the GBM microenvironment including recruited MSCs. MSCs engineered to drive <i>NIS</i> expression in response to IL-6 promoter activation offer the possibility of a new tumor-targeted gene therapy approach of GBM. Therefore, MSCs were stably transfected with an NIS-expressing plasmid controlled by the human IL-6 promoter (IL-6-NIS-MSCs) and systemically applied in mice carrying orthotopic GBM. Enhanced radiotracer uptake by <sup>18</sup>F-Tetrafluoroborate-PET/magnetic resonance imaging (MRI) was detected in tumors after IL-6-NIS-MSC application as compared with mice that received wild-type MSCs. <i>Ex vivo</i> analysis of tumors and non-target organs showed tumor-specific NIS protein expression. Subsequent <sup>131</sup>I therapy after IL-6-NIS-MSC application resulted in significantly delayed tumor growth assessed by MRI and improved median survival up to 60% of GBM-bearing mice as compared with controls. In conclusion, the application of MSC-mediated <i>NIS</i> gene therapy focusing on IL-6 biology-induced <i>NIS</i> transgene expression represents a promising approach for GBM treatment.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"238-253"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/aa/12/main.PMC10493263.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10579245","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}
Jia Yi, Peizhe Lin, Qingbo Li, Ao Zhang, Xianbin Kong
{"title":"A new strategy for treating colorectal cancer: Regulating the influence of intestinal flora and oncolytic virus on interferon.","authors":"Jia Yi, Peizhe Lin, Qingbo Li, Ao Zhang, Xianbin Kong","doi":"10.1016/j.omto.2023.08.010","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.010","url":null,"abstract":"<p><p>Colorectal cancer (CRC) has the third highest incidence and the second highest mortality in the world, which seriously affects human health, while current treatments methods for CRC, including systemic therapy, preoperative radiotherapy, and surgical local excision, still have poor survival rates for patients with metastatic disease, making it critical to develop new strategies for treating CRC. In this article, we found that the gut microbiota can modulate the signaling pathways of cancer cells through direct contact with tumor cells, generate inflammatory responses and oxidative stress through interactions between the innate and adaptive immune systems, and produce diverse metabolic combinations to trigger specific immune responses and promote the initiation of systemic type I interferon (IFN-I) and anti-viral immunity. In addition, oncolytic virus-mediated immunotherapy for regulating oncolytic virus can directly lyse tumor cells, induce the immune activity of the body, interact with interferon, inhibit the anti-viral effect of IFN-I, and enhance the anti-tumor effect of IFN-II. Interferon plays an important role in the anti-tumor process. We put forward that exploring the effects of intestinal flora and oncolytic virus on interferon to treat CRC is a promising therapeutic option.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"254-274"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2d/12/main.PMC10493895.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10596819","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}
Tiantian Cui, Sergio Corrales-Guerrero, Veronica Castro-Aceituno, Sindhu Nair, Daniel C Maneval, Curtis Monnig, Patrick Kearney, Sam Ellis, Nicholas Raheja, Neil Raheja, Terence M Williams
{"title":"JNTX-101, a novel albumin-encapsulated gemcitabine prodrug, is efficacious and operates via caveolin-1-mediated endocytosis.","authors":"Tiantian Cui, Sergio Corrales-Guerrero, Veronica Castro-Aceituno, Sindhu Nair, Daniel C Maneval, Curtis Monnig, Patrick Kearney, Sam Ellis, Nicholas Raheja, Neil Raheja, Terence M Williams","doi":"10.1016/j.omto.2023.08.008","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.008","url":null,"abstract":"<p><p>Albumin is an attractive candidate carrier for the development of novel therapeutic drugs. Gemcitabine has been FDA approved for the treatment of solid tumors; however, new drugs that optimize gemcitabine delivery are not available for clinical use. The aim of this study was to test the efficacy of a novel albumin-encapsulated gemcitabine prodrug, JNTX-101, and investigate whether Cav-1 expression predicts the therapeutic efficacy of JNTX-101. We first determined the treatment efficacy of JNTX-101 in a panel of pancreatic/lung cancer cell lines and found that increases in Cav-1 expression resulted in higher uptake of albumin, while Cav-1 depletion attenuated the sensitivity of cells to JNTX-101. In addition, decreased Cav-1 expression markedly reduced JNTX-101-induced apoptotic cell death in a panel of cells, particularly in low-serum conditions. Furthermore, we tested the therapeutic efficacy of JNTX-101 in xenograft models and the role of Cav-1 in JNTX-101 sensitivity using a Tet-on-inducible tumor model <i>in vivo</i>. Our data suggest that JNTX-101 effectively inhibits cell viability and tumor growth, and that Cav-1 expression dictates optimal sensitivity to JNTX-101. These data indicate that Cav-1 correlates with JNTX-101 sensitivity, especially under nutrient-deprived conditions, and supports a role for Cav-1 as a predictive biomarker for albumin-encapsulated therapeutics such as JNTX-101.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"181-192"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/14/40/main.PMC10477748.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10550709","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}
Baijin Xia, Keming Lin, Xuemei Wang, FeiLi Chen, Mo Zhou, Yuzhuang Li, Yingtong Lin, Yidan Qiao, Rong Li, Wanying Zhang, Xin He, Fan Zou, Linghua Li, Lijuan Lu, Cancan Chen, WenYu Li, Hui Zhang, Bingfeng Liu
{"title":"Nanobody-derived bispecific CAR-T cell therapy enhances the anti-tumor efficacy of T cell lymphoma treatment.","authors":"Baijin Xia, Keming Lin, Xuemei Wang, FeiLi Chen, Mo Zhou, Yuzhuang Li, Yingtong Lin, Yidan Qiao, Rong Li, Wanying Zhang, Xin He, Fan Zou, Linghua Li, Lijuan Lu, Cancan Chen, WenYu Li, Hui Zhang, Bingfeng Liu","doi":"10.1016/j.omto.2023.07.007","DOIUrl":"https://doi.org/10.1016/j.omto.2023.07.007","url":null,"abstract":"<p><p>T cell lymphoma (TCL) is a highly heterogeneous group of diseases with a poor prognosis and low 5-year overall survival rate. The current therapeutic regimens have relatively low efficacy rates. Clinical studies of single-target chimeric antigen receptor T cell (CAR-T cell) therapy in T lymphocytes require large and multiple infusions, increasing the risks and cost of treatment; therefore, optimizing targeted therapy is a way to improve overall prognosis. Despite significant advances in bispecific CAR-T cell therapy to avoid antigen escape in treatment of B cell lymphoma, applying this strategy to TCL requires further investigation. Here, we constructed an alpaca nanobody (Nb) phage library and generated high-affinity and -specificity Nbs targeting CD30 and CD5, respectively. Based on multiple rounds of screening, bispecific NbCD30-CD5-CAR T cells were constructed, and their superior anti-tumor effect against TCL was validated <i>in vitro</i> and <i>in vivo</i>. Our findings demonstrated that Nb-derived bispecific CAR-T cells significantly improved anti-tumor efficacy in TCL treatment compared with single-target CAR-T cells and bispecific single chain variable fragment (scFv)-derived CAR-T cells. Because Nbs are smaller and less immunogenic, the synergistic effect of Nb-based bispecific CAR-T cells may improve their safety and efficacy in future clinical applications.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"86-102"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/53/6d/main.PMC10427987.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10046528","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}
Janina Marek, Lorenz Hanesch, Teresa Krabbe, Nadia El Khawanky, Simon Heidegger, Jennifer Altomonte
{"title":"Oncolytic virotherapy with chimeric VSV-NDV synergistically supports RIG-I-dependent checkpoint inhibitor immunotherapy.","authors":"Janina Marek, Lorenz Hanesch, Teresa Krabbe, Nadia El Khawanky, Simon Heidegger, Jennifer Altomonte","doi":"10.1016/j.omto.2023.08.001","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.001","url":null,"abstract":"<p><p>Unraveling the complexities of the tumor microenvironment (TME) and its correlation with responsiveness to immunotherapy has become a main focus in overcoming resistance to such treatments. Targeting tumor-intrinsic retinoic acid-inducible gene-I (RIG-I), a sensor for viral RNA, was shown to transform the TME from an immunogenically \"cold\" state to an inflamed, \"hot\" lesion, which we demonstrated previously to be a crucial mediator of the efficacy of immune checkpoint inhibition with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4). In this study, we focus on the chimeric oncolytic virus vesicular stomatitis virus (VSV)-Newcastle disease virus (NDV), comprised of genetic components of VSV and NDV, and we investigate its utility to support tumor-intrinsic RIG-I-dependent therapy with anti-CTLA-4. Overall, we demonstrate that treatment with VSV-NDV efficiently delays tumor growth and significantly prolongs survival in a murine model of malignant melanoma, which was further enhanced in combination with anti-CTLA-4. Although the direct oncolytic and pro-inflammatory effects of VSV-NDV therapy were independent of RIG-I activation, the synergism with anti-CTLA-4 therapy and associated activation of tumor-specific T cells was critically dependent on active RIG-I signaling in tumor cells. This work highlights the therapeutic value of utilizing an immune-stimulatory oncolytic virus to sensitize tumors to immune checkpoint inhibition.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"117-131"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/08/dc/main.PMC10465858.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10134686","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}
Shiyu Liu, Fan Li, Li Deng, Qiongqiong Ma, Wenyi Lu, Zhuoqian Zhao, Huanzhen Liu, Yixuan Zhou, Manli Hu, Hui Wang, Yingbin Yan, Mingfeng Zhao, Hongkai Zhang, Mingjuan Du
{"title":"Claudin18.2 bispecific T cell engager armed oncolytic virus enhances antitumor effects against pancreatic cancer.","authors":"Shiyu Liu, Fan Li, Li Deng, Qiongqiong Ma, Wenyi Lu, Zhuoqian Zhao, Huanzhen Liu, Yixuan Zhou, Manli Hu, Hui Wang, Yingbin Yan, Mingfeng Zhao, Hongkai Zhang, Mingjuan Du","doi":"10.1016/j.omto.2023.08.011","DOIUrl":"https://doi.org/10.1016/j.omto.2023.08.011","url":null,"abstract":"<p><p>Bispecific T cell engagers (BiTEs) represent a promising immunotherapy, but their efficacy against immunologically cold tumors such as pancreatic ductal adenocarcinoma remains unclear. Oncolytic viruses (OVs) can transform the immunosuppressive tumor microenvironment into the active state and also serve as transgene vectors to selectively express the desired genes in tumor cells. This study aimed to investigate whether the therapeutic benefits of tumor-targeting Claudin18.2 BiTE can be augmented by combining cancer selectively and immune-potentiating effects of OVs. Claudin18.2/CD3 BiTE was inserted into herpes simplex virus type 1 (HSV-1) to construct an OV-BiTE. Its expression and function were assessed using reporter cells and peripheral blood mononuclear cell (PBMC) co-culture assays. Intratumoral application of OV-BiTE restrained tumor growth and prolonged mouse survival compared with the unarmed OV in xenograft models and syngeneic mice bearing CLDN18.2-expressing KPC or Pan02 pancreatic cancer cells. Flow cytometry of tumor-infiltrating immune cells suggested both OV-BiTE and the unarmed OV remodeled the tumor microenvironment by increasing CD4+ T cell infiltration and decreasing regulatory T cells. OV-BiTE further reprogrammed macrophages to a more pro-inflammatory antitumor state, and OV-BiTE-induced macrophages exhibited greater cytotoxicity on the co-cultured tumor cell. This dual cytotoxic and immunomodulatory approach warrants further development for pancreatic cancer before clinical investigation.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"275-285"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5b/b3/main.PMC10493249.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10596823","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}
Chiara F Magnani, Renier Myburgh, Silvan Brunn, Morgane Chambovey, Marianna Ponzo, Laura Volta, Francesco Manfredi, Christian Pellegrino, Steve Pascolo, Csaba Miskey, Zoltán Ivics, Judith A Shizuru, Dario Neri, Markus G Manz
{"title":"Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells.","authors":"Chiara F Magnani, Renier Myburgh, Silvan Brunn, Morgane Chambovey, Marianna Ponzo, Laura Volta, Francesco Manfredi, Christian Pellegrino, Steve Pascolo, Csaba Miskey, Zoltán Ivics, Judith A Shizuru, Dario Neri, Markus G Manz","doi":"10.1016/j.omto.2023.07.003","DOIUrl":"https://doi.org/10.1016/j.omto.2023.07.003","url":null,"abstract":"<p><p>Discrimination between hematopoietic stem cells and leukemic stem cells remains a major challenge for acute myeloid leukemia immunotherapy. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells before consolidation with allogeneic hematopoietic stem cell transplantation in absence of cytotoxic conditioning. Here we exploit non-viral technology to achieve early termination of CAR T cell activity to prevent incoming graft rejection. Transient expression of an anti-CD117 CAR by mRNA conferred T cells the ability to eliminate CD117+ targets <i>in vitro</i> and <i>in vivo</i>. As an alternative approach, we used a Sleeping Beauty transposon vector for the generation of CAR T cells incorporating an inducible Caspase 9 safety switch. Stable CAR expression was associated with high proportion of T memory stem cells, low levels of exhaustion markers, and potent cellular cytotoxicity. Anti-CD117 CAR T cells mediated depletion of leukemic cells and healthy hematopoietic stem cells in NSG mice reconstituted with human leukemia or CD34+ cord blood cells, respectively, and could be terminated <i>in vivo</i>. The use of a non-viral technology to control CAR T cell pharmacokinetic properties is attractive for a first-in-human study in patients with acute myeloid leukemia prior to hematopoietic stem cell transplantation.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"56-71"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10117212","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}
Murad Alahdal, Roshane A Perera, Marcio Covas Moschovas, Vipul Patel, Ranjan J Perera
{"title":"Current advances of liquid biopsies in prostate cancer: Molecular biomarkers.","authors":"Murad Alahdal, Roshane A Perera, Marcio Covas Moschovas, Vipul Patel, Ranjan J Perera","doi":"10.1016/j.omto.2023.07.004","DOIUrl":"https://doi.org/10.1016/j.omto.2023.07.004","url":null,"abstract":"<p><p>Prostate cancer (PCa) incidence is increasing and endangers men's lives. Early detection of PCa could improve overall survival (OS) by preventing metastasis. The prostate-specific antigen (PSA) test is a popular screening method. Several advisory groups, however, warn against using the PSA test due to its high false positive rate, unsupported outcome, and limited benefit. The number of disease-related biopsies performed annually far outweighs the number of diagnoses. Thus, there is an urgent need to develop accurate diagnostic biomarkers to detect PCa and distinguish between aggressive and indolent cancers. Recently, non-coding RNA (ncRNA), circulating tumor DNA (ctDNA)/ctRNA, exosomes, and metabolomic biomarkers in the liquid biopsies (LBs) of patients with PCa showed significant differences and clinical benefits in diagnosis, prognosis, and monitoring response to therapy. The analysis of urinary exosomal ncRNA presented a substantial correlation among Exos-miR-375 downregulation, clinical T stage, and bone metastases of PCa. Furthermore, the expression of miR-532-5p in urine samples was a vital predictive biomarker of PCa progression. Thus, this review focuses on promising molecular and metabolomic biomarkers in LBs from patients with PCa. We thoroughly addressed the most recent clinical findings of LB biomarker use in diagnosing and monitoring PCa in early and advanced stages.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"27-38"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/6c/main.PMC10415624.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9988923","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}
Jaeryuk Kim, Miyoung Park, Gyungwon Baek, Joo-Il Kim, Euna Kwon, Byeong-Cheol Kang, Jong-Il Kim, Hyoung Jin Kang
{"title":"Tagmentation-based analysis reveals the clonal behavior of CAR-T cells in association with lentivector integration sites.","authors":"Jaeryuk Kim, Miyoung Park, Gyungwon Baek, Joo-Il Kim, Euna Kwon, Byeong-Cheol Kang, Jong-Il Kim, Hyoung Jin Kang","doi":"10.1016/j.omto.2023.05.004","DOIUrl":"https://doi.org/10.1016/j.omto.2023.05.004","url":null,"abstract":"<p><p>Integration site (IS) analysis is essential in ensuring safety and efficacy of gene therapies when integrating vectors are used. Although clinical trials of gene therapy are rapidly increasing, current methods have limited use in clinical settings because of their lengthy protocols. Here, we describe a novel genome-wide IS analysis method, \"detection of the integration sites in a time-efficient manner, quantifying clonal size using tagmentation sequencing\" (DIStinct-seq). In DIStinct-seq, a bead-linked Tn5 transposome is used, allowing the sequencing library to be prepared within a single day. We validated the quantification performance of DIStinct-seq for measuring clonal size with clones of known IS. Using <i>ex vivo</i> chimeric antigen receptor (CAR)-T cells, we revealed the characteristics of lentiviral IS. We then applied it to CAR-T cells collected at various times from tumor-engrafted mice, detecting 1,034-6,233 IS. Notably, we observed that the highly expanded clones had a higher integration frequency in the transcription units and vice versa in genomic safe harbors (GSH). Also, in GSH, persistent clones had more frequent IS. Together with these findings, the new IS analysis method will help to improve the safety and efficacy of gene therapies.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"1-13"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1f/08/main.PMC10285042.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9713501","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}
Jérémy Béguin, Eve Laloy, Sandrine Cochin, Murielle Gantzer, Isabelle Farine, Christelle Pichon, Baptiste Moreau, Johann Foloppe, Jean-Marc Balloul, Christelle Machon, Jérôme Guitton, Dominique Tierny, Bernard Klonjkowski, Eric Quéméneur, Christelle Maurey, Philippe Erbs
{"title":"Oncolytic virotherapy with intratumoral injection of vaccinia virus TG6002 and 5-fluorocytosine administration in dogs with malignant tumors.","authors":"Jérémy Béguin, Eve Laloy, Sandrine Cochin, Murielle Gantzer, Isabelle Farine, Christelle Pichon, Baptiste Moreau, Johann Foloppe, Jean-Marc Balloul, Christelle Machon, Jérôme Guitton, Dominique Tierny, Bernard Klonjkowski, Eric Quéméneur, Christelle Maurey, Philippe Erbs","doi":"10.1016/j.omto.2023.07.005","DOIUrl":"https://doi.org/10.1016/j.omto.2023.07.005","url":null,"abstract":"<p><p>TG6002 is an oncolytic vaccinia virus expressing FCU1 protein, which converts 5-fluorocytosine into 5-fluorouracil. The study objectives were to assess tolerance, viral replication, 5-fluorouracil synthesis, and tumor microenvironment modifications to treatment in dogs with spontaneous malignant tumors. Thirteen dogs received one to three weekly intratumoral injections of TG6002 and 5-fluorocytosine. The viral genome was assessed in blood and tumor biopsies by qPCR. 5-Fluorouracil concentrations were measured in serum and tumor biopsies by liquid chromatography or high-resolution mass spectrometry. Histological and immunohistochemical analyses were performed. The viral genome was detected in blood (7/13) and tumor biopsies (4/11). Viral replication was suspected in 6/13 dogs. The median intratumoral concentration of 5-fluorouracil was 314 pg/mg. 5-Fluorouracil was not detected in the blood. An increase in necrosis (6/9) and a downregulation of intratumoral regulatory T lymphocytes (6/6) were observed. Viral replication, 5-fluorouracil synthesis, and tumor microenvironment changes were more frequently observed with higher TG6002 doses. This study confirmed the replicative properties, targeted chemotherapy synthesis, and reversion of the immunosuppressive tumor microenvironment in dogs with spontaneous malignant tumors treated with TG6002 and 5-fluorocytosine.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":"30 ","pages":"103-116"},"PeriodicalIF":5.7,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e4/68/main.PMC10448017.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10105811","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}
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