Pub Date : 2023-08-28eCollection Date: 2023-09-21DOI: 10.1016/j.omto.2023.08.012
Md Obaidul Islam, Krishnapriya Thangaretnam, Heng Lu, Dunfa Peng, Mohammed Soutto, Wael El-Rifai, Silvia Giordano, Yuguang Ban, Xi Chen, Daniel Bilbao, Alejandro V Villarino, Stephan Schürer, Peter J Hosein, Zheng Chen
Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment in vitro. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel in vivo. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival in vivo. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.
{"title":"Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma.","authors":"Md Obaidul Islam, Krishnapriya Thangaretnam, Heng Lu, Dunfa Peng, Mohammed Soutto, Wael El-Rifai, Silvia Giordano, Yuguang Ban, Xi Chen, Daniel Bilbao, Alejandro V Villarino, Stephan Schürer, Peter J Hosein, Zheng Chen","doi":"10.1016/j.omto.2023.08.012","DOIUrl":"10.1016/j.omto.2023.08.012","url":null,"abstract":"<p><p>Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment <i>in vitro</i>. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel <i>in vivo</i>. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival <i>in vivo</i>. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/66/86/main.PMC10507159.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41139219","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}
Pub Date : 2023-08-15eCollection Date: 2023-09-21DOI: 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
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.
{"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":"<p><p>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<sup>+</sup> patient-derived models. Despite using sensitive immunopeptidomics, we could not detect the H3.3K27M<sub>26-35</sub>-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 K27M<sub>26-35</sub>-HLA-A∗02:01 peptide. These results suggest that targeting the H3 K27M<sub>26-35</sub> 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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"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}
Pub Date : 2023-07-19eCollection Date: 2023-09-21DOI: 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
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.
为限制肿瘤感染而改良的肿瘤溶解病毒是一种很有前景的癌症免疫疗法,但人们对驱动其在肿瘤微环境中的活性和结果的因素还有很多不了解。在这里,我们报告了溶瘤性单纯疱疹病毒 C134,它以前在胶质母细胞瘤小鼠模型中发挥了依赖 T 细胞的疗效,但在髓母细胞瘤小鼠模型中却发挥了不依赖 T 细胞的疗效,这表明这种溶瘤病毒在不同的肿瘤中使用了不同的机制。我们研究了 C134 在小鼠髓母细胞瘤中的表现,利用单细胞 RNA 测序,以全转录组分辨率绘制了 C134 诱导的跨细胞类型、时间点和髓母细胞瘤亚组模型的基因表达变化图。我们的研究详述了大量溶瘤病毒诱导的髓母细胞瘤浸润免疫细胞转录重塑,10个单核细胞和巨噬细胞亚群对C134共同表现出M1样反应,并建议将C134作为一种潜在的髓母细胞瘤新疗法进行研究。
{"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":"<p><p>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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"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}
Pub Date : 2023-06-15DOI: 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
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.
{"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":"<p><p>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 <i>in vitro</i> and <i>in vivo</i> 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. <i>In vitro</i> studies indicated that 4T1 breast cancer cells were more susceptible to the developed recombinant viruses. <i>In vivo</i> 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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"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}
Pub Date : 2023-06-15DOI: 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
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.
{"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":"<p><p>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 <i>in vitro</i> and <i>in vivo</i> against two CD19-positive cancer cell lines. In addition, expression and secretion of a CD19 sBite enhances γδ T cell cytotoxicity, both <i>in vitro</i> and <i>in vivo</i>, 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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"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}
Pub Date : 2023-06-15DOI: 10.1016/j.omto.2023.04.004
Zhiyuan Mao, John K Lee
{"title":"Expanding the landscape of TCR gene therapy targeting MAGE.","authors":"Zhiyuan Mao, John K Lee","doi":"10.1016/j.omto.2023.04.004","DOIUrl":"https://doi.org/10.1016/j.omto.2023.04.004","url":null,"abstract":"","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"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/5d/18/main.PMC10195836.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9503868","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}
Pub Date : 2023-06-15DOI: 10.1016/j.omto.2023.02.010
Joseph R Caporale, Dean A Lee
{"title":"Attack of the clones: An NK cell origins story.","authors":"Joseph R Caporale, Dean A Lee","doi":"10.1016/j.omto.2023.02.010","DOIUrl":"https://doi.org/10.1016/j.omto.2023.02.010","url":null,"abstract":"","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9219752","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}
Pub Date : 2023-06-15DOI: 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
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.
{"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":"<p><p>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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"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}