CRISPR-based gene disruption coupled to targeted integration of novel, high-avidity, natural T cell receptors to WT1 for acute leukemia
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ABSTRACT:
PROVIDER: PRJNA783315 | ENA |
REPOSITORIES: ENA
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Project description:CRISPR-based gene disruption coupled to targeted integration of novel, high-avidity, natural T cell receptors to WT1 for acute leukemia
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Project description:Renal proximal tubule cell state and metabolism are coupled by nuclear receptors
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Project description:Interventions: A patient is vaccinated with Montanide ISA51-adjuvanted WT1 Trio cancer vaccine consisting of two WT1 CTL peptides (WT1-126 and WT1-235) and one WT1 HTL peptide (WT1-332) (2mg each) seven times at the interval of two weeks.
Primary outcome(s): Induction of WT1-specific immune responses assessed by WT1-related tests such as WT1-DTH skin reaction and serum levels of WT1 peptide IgG autoantibody at 1M, 2M, and 3M of WT1 Trio vaccine.
Study Design: Single arm Non-randomized
| 2638832 | ecrin-mdr-crc
Project description:K-ras is one of the most frequently mutated human oncogenes. Activation of K-ras can lead to either senescence or proliferation in primary cells. The precise mechanism governing these distinct outcomes remains unclear. Here we utilized a loss-of-function screen to assess the role of specific genes identified as potential key regulators of K-ras driven oncogenesis. Using this approach, we identify the transcription factor Wt1 as an inhibitor of senescence in primary cells expressing oncogenic K-ras. Deletion or suppression of Wt1 expression leads to senescence of primary cells expressing oncogenic K-ras under the control of the native promotor at physiological levels, but has no effect on cells expressing wild-type K-ras. Wt1 contributes to K-ras driven lung tumorigenesis in vivo and loss of Wt1 is specifically deleterious to human lung cancer cell lines that are dependent on oncogenic K-ras. Taken together, these observations reveal a novel role for Wt1 as a key regulator of the complex genetic network required for the oncogenic effect of the small GTPase K-ras. We compare the expression profiles of Wild type, K-ras mutant, Wt1-null, and double K-ras mutant/Wt1-null mouse embryonic fibroblasts (MEFs). The study provides insights into the transcriptional role of Wt1 in the context of oncogenic K-ras.
2010-03-01 | GSE15325 | GEO
Project description:Interventions: A patient is vaccinated with Montanide ISA51-adjuvanted WT1 Trio cancer vaccine consisting of two WT1 CTL peptides (WT1-126 and WT1-235) and one WT1 HTL peptide (WT1-332) (2mg each) seven times at the interval of two to four weeks. The interval can be changed within a range from one to 16 weeks.
Primary outcome(s): Induction of WT1-specific immune responses assessed by WT1-related tests such as WT1-DTH skin reaction, serum levels of WT1 peptide IgG autoantibody, and frequency of WT1-CTL in PB * This is evaluated at the interval ranging from 6 to 12 months.
Study Design: Single arm Non-randomized
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Project description:A major barrier of vaccines as cancer treatment is their failure to activate and maintain a complete cancer-specific CD8+ effector T cell repertoire. Low avidity T cells are more likely to escape clonal deletion in the thymus when compared to higher avidity T cells, and therefore comprise the major population of effector T cells available for activation in cancer patients. However, low avidity T cells fail to traffic into the tumor microenvironment and function in eradicating tumor under optimal vaccination conditions as opposed to higher avidity T cells that escape clonal deletion and do function in tumor killing. We utilized high and low avidity TCR transgenic CD8+ T cells specific for the immunodominant epitope of HER-2/neu (RNEU420-429) to identify signaling pathways responsible for the inferior activity of low avidity T cells. Adoptive transfer of these cells into tumor-bearing vaccinated mice identified members of apoptosis pathways as being upregulated in low avidity T cells. The increased expression of pro-apoptotic proteins by low avidity T cells promoted their own cell death and also that of other tumor-specific CD8+ T cells within their local environment. Importantly, this pro-apoptotic effect was overcome using a strong costimulatory signal that prevents activation-induced cell death and enables low avidity T cells to traffic into the tumor and assist in tumor clearance. These findings identify new therapeutic opportunities for activating the most potent anticancer T cell responses. High and low avidity T cells were isolated from TCR transgenic mice and adoptively transferred into Cy-treated, vaccinated, neu-N mice. Three days after adoptive transfer T cells were isolated from the tumor draining nodes and RNA was extracted for gene expression analysis.
2014-01-14 | E-GEOD-54020 | biostudies-arrayexpress
Project description:Gain-of-function mutations in exon 3 of beta-catenin (CTNNB1) are specific for Wilms' tumors that have lost WT1, but 50% of WT1-mutant cases lack such "hot spot" mutations. To ask whether stabilization of beta-catenin might be essential after WT1 loss, and to identify downstream target genes, we compared expression profiles in WT1-mutant versus WT1 wild-type Wilms' tumors. Supervised and nonsupervised hierarchical clustering of the expression data separated these two classes of Wilms' tumor. The WT1-mutant tumors overexpressed genes encoding myogenic and other transcription factors (MOX2, LBX1, SIM2), signaling molecules (TGFB2, FST, BMP2A), extracellular Wnt inhibitors (WIF1, SFRP4), and known beta-catenin/TCF targets (FST, CSPG2, CMYC). Beta-Catenin/TCF target genes were overexpressed in the WT1-mutant tumors even in the absence of CTNNB1 exon 3 mutations, and complete sequencing revealed gain-of-function mutations elsewhere in the CTNNB1 gene in some of these tumors, increasing the overall mutation frequency to 75%. Lastly, we identified and validated a novel direct beta-catenin target gene, GAD1, among the WT1-mutant signature genes. These data highlight two molecular classes of Wilms' tumor, and indicate strong selection for stabilization of beta-catenin in the WT1-mutant class. Beta-Catenin stabilization can initiate tumorigenesis in other systems, and this mechanism is likely critical in tumor formation after loss of WT1. Experiment Overall Design: Identification of WNT/Beta-Catenin or WT1 target genes. 39 individual samples.
2008-06-14 | E-GEOD-6120 | biostudies-arrayexpress