An Open-Label, Multiple-Center, Phase IIa/IIb Clinical Trial to Evaluate the Efficacy, Safety and Tolerability of VG161 as Monotherapy and in Combination With Nivolumab for Treatment of Patients With Hepatocellular Carcinoma or Intrahepatic Cholangiocarcinoma

Safety Run-in Cohort (cohort 1):
10 patients will be treated with IT injection of VG161 in the cohort 1 at dose level of 1.0x10E8 PFU x 3 days.
Monotherapy Cohorts (Cohort 2 and 3) Cohort 2 (HCC) This part is a single-agent, single one-dose level and single-arm design. Approximately 39 subjects will be enrolled in the study to receive VG161. In the first stage, 21 subjects will be enrolled. If there is only 1 or fewer subjects has been observed with objective response and no more than 12 (<13) subjects have PFS longer than 3 months, the trial will be stopped. Otherwise, this study will continue to enter the second stage, and 18 additional subjects will be added, and the total number of trial subjects will reach 39.
Cohort 3 (ICC) This part is a single-agent, single one-dose level and single-arm design. The trial will be carried out in two periods. In the first period, a total of 20 subjects will be enrolled. If there is only 1 or fewer response case in the 20 subjects, the trial will be stopped to investigate the efficacy of the IP, otherwise, subjects will continue to enter the second period, and 13 additional subjects will be added, and the total number of trial cases will reach 33.
Cohort 4 (ICC and HCC) Combination with Nivolumab Combination cohort and subjects will receive VG161 at the same schedule as the monotherapy cohorts and 240 mg of intravenous Nivolumab on days 8 and 15 of each treatment cycle. The Nivolumab dose can be changed to 480 mg every 4 weeks after cycle one based on investigator's discretion.

开始日期2024-01-24

申办/合作机构

Virogin Biotech Ltd.初创企业

CTR20233149 / Recruiting临床1/2期

VG161联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的开放的Ib/IIa 期临床试验

Ib期主要目的：评价VG161连续多次肿瘤内注射给药联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的安全性和耐受性，探索联合治疗最适合的II期推荐剂量（RP2D）。次要目的： 1）初步评价VG161联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的抗肿瘤活性；2）监测药效学相关的免疫学指标变化； 3）评价I型单纯疱疹病毒抗体滴度水平对VG161安全性、有效性的影响。IIa期主要目的：评价VG161连续多次肿瘤内注射给药联合卡瑞利珠单抗治疗晚期原发性肝细胞癌患者的有效性，主要观察指标是客观缓解率（ORR）。次要目的：1）评价联合治疗有效性的次要观察指标，包括疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）、缓解持续时间（DOR）；2）监测药效学相关的免疫学指标变化；3）进一步评价 VG161联合卡瑞利珠单抗治疗的安全性。4）评价I型单纯疱疹病毒抗体滴度水平对VG161安全性、有效性的影响

开始日期2023-12-04

申办/合作机构

中生复诺健生物科技（上海）有限公司

100 项与 IL-12R x IL-15Rα 相关的临床结果

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100 项与 IL-12R x IL-15Rα 相关的转化医学

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0 项与 IL-12R x IL-15Rα 相关的专利（医药）

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项与 IL-12R x IL-15Rα 相关的文献（医药）

2023-03-01·International Immunopharmacology

Integrated analysis of ATAC-seq and RNA-seq reveals the transcriptional regulation network in SLE

Article

作者: Wu, Jiali ; Feng, Delong ; Hu, Zhi ; Li, Yuwei ; Yu, Yaqin ; Long, Haojun ; Lu, Qianjin ; Zhao, Ming

BACKGROUNDCD4⁺ T cells have a vital role in the pathogenesis of systemic lupus erythematosus (SLE), abnormal gene expression in CD4⁺ T cells partly accounting for dysfunctional CD4⁺T cells. However, the underying regulatory mechanisms of abnormal gene expression in CD4⁺ T cells derived from SLE patients are not fully understood.METHODSThe peripheral blood CD4⁺ T cells were acquired from 4 SLE patients and 4 matched healthy controls. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) was conducted to screen differentially accessible chromatin regions between SLE and normals, and motif prediction was used to identify potentially key transcription factors (TFs) involved in CD4⁺T dysfunction. RNA sequencing (RNA-seq) was performed to screen differentially expressed genes in SLE CD4⁺T cells. ATAC-seq and RNA-seq were integrated to further analyze the relationship between chromatin accessibility and gene expression. KEGG pathway enrichment analysis was to determine enriched pathways of interactions between all predicted TFs and differentially expressed genes (DEGs). Meanwhile, the expression changes of target genes followed by siRNA knockdown of the predicted TF were experimentally verified by qPCR. Finally, the H3K27ac modification levels of immune-related genes with open chromatin and up-regulated expression in SLE CD4⁺T cells was detected by ChIP-qPCR.RESULTSWe identified 3067 differentially accessible regions (DARs) and 1292 DEGs. TF prediction and functional enrichment analyses showed the TF-gene interaction networks were enriched predominantly in T helper 17 (Th17) cell differentiation, the cell cycle and some signaling pathways. Top 5 TFs were predicted based on overlapping genes between the DAR-related genes and the DEGs: ZNF770, THAP11, ZBTB14, ETV1, POU3F1. Validation experiments indicated that the expression of TRIM25, CD163, BST2, IFIT5, IFITM3, OASL, TBX21, IL15RA and IL12RB2 was significantly downregulated in CD4⁺Tcells with ZNF770 knockdown. H3K27ac showed significantly higher levels in the promoter regions of KLF4 and MX2 in SLE CD4⁺ T cells.CONCLUSIONThese DARs associated with this disease may become targets for future treatment of SLE.

2020-03-01·Physiological Genomics3区 · 生物学

Transcriptomic signature of gut microbiome-contacting cells in colon of spontaneously hypertensive rats

3区 · 生物学

Article

作者: Li, Hongbao ; Oliveira, Aline C. ; Richards, Elaine M. ; Pepine, Carl J. ; Yang, Tao ; Raizada, Mohan K. ; Goel, Ruby

Fecal matter transfer from hypertensive patients and animals into normotensive animals increases blood pressure, strengthening the evidence for gut-microbiota interactions in the control of blood pressure. However, cellular and molecular events involved in gut dysbiosis-associated hypertension remain poorly understood. Therefore, our objective in this study was to use gene expression profiling to characterize the gut epithelium layer in the colon in hypertension. We observed significant suppression of components of T cell receptor (TCR) signaling in the colonic epithelium of spontaneously hypertensive rats (SHR) when compared with Wistar Kyoto (WKY) normotensive rats. Western blot analysis confirmed lower expression of key proteins including T cell surface glycoprotein CD3 gamma chain (Cd3g) and lymphocyte cytosolic protein 2 (Lcp2). Furthermore, lower expression of cytokines and receptors responsible for lymphocyte proliferation, differentiation, and activation (e.g., Il12r, Il15ra, Il7, Il16, Tgfb1) was observed in the colonic epithelium of the SHR. Finally, Alpi and its product, intestinal alkaline phosphatase, primarily localized in the epithelial cells, were profoundly lower in the SHR. These observations demonstrate that the colonic epithelium undergoes functional changes linked to altered immune, barrier function, and dysbiosis in hypertension.

2014-03-15·International Journal of Cancer1区 · 医学

Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry

1区 · 医学

Article

作者: Ambrosone, Christine B. ; Hong, Chi‐Chen ; Pawlish, Karen ; Bovbjerg, Dana H. ; Cabasag, Citadel ; Jandorf, Lina ; Yao, Song ; Bandera, Elisa V. ; Ciupak, Gregory ; Zirpoli, Gary ; Quan, Lei ; Coignet, Jean‐Gabriel ; Davis, Warren ; Hwang, Helena ; Gong, Zhihong ; Sucheston, Lara ; Roberts, Michelle

Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine‐related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell‐mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P‐trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER‐positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER‐positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER‐negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status.