Longitudinal serum auto-antibody response during HER2-CAR T cell therapy in a child with rhabdomyosarcoma identified using Protein microarray
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ABSTRACT:
ORGANISM(S): other sequences Homo sapiens
PROVIDER: GSE152029 | GEO | 2020/06/09
REPOSITORIES: GEO
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Project description:Longitudinal serum auto-antibody response during HER2-CAR T cell therapy in a child with rhabdomyosarcoma identified using Protein microarray
| PRJNA638134 | ENA
Project description:To further development of different gene expression between the PTL-Her2-CAR-T cells (knockdown of PD-1, Tim-3, Lag-3 by shRNA-clusters in Her2-CAR-T cells) and Her2-CAR-T cells, we have employed whole genome microarray expression profiling as a discovery platform.
2019-09-23 | GSE131107 | GEO
Project description:Purpose: Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53 specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. Experimental Design: IgG p53 autoantibodies (p53-AAb), were quantified in 412 serum saples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer. To determine if patients generated mutation specific autoantibodies we designed a panel of the most relevant 51 p53 point mutant proteins, to be displayed on custom programmable protein microarrays. To determine the epitope specificity we displayed 12 overlapping tiling fragments and 38 N- and C-terminal deletions spanning the length of the wild-type p53 proteins. Results: We detected p53-AAb with sensitivities of 58.8% (ovarian), 22% (pancreatic), 32% (triple negative breast cancer), and 10.2% (HER2+ breast cancer) at 94% specificity. Sera with p53-AAb contained broadly-reactive autoantibodies to 51 displayed p53 mutant proteins, demonstrating a polyclonal response to common epitopes. All p53-AAb displayed broad polyclonal immune response to both continuous and discontinuous epitopes at the N- and C-terminus as well as the DNA binding domain. Conclusion and clinical relevance: In this comprehensive analysis, mutations in tumor p53 induce strong, polyclonal autoantibodies with broadly reactive epitope specificity. The immunoreactivity was compared between 60 pancreactic ductal adenocarcinoma cases and 63 benign pancreatic disease controls against 52 unique mutant p53 and 379 human proteins that were printed on microscope slides. [Contributor] Arizona State University
2016-06-01 | E-GEOD-77949 | biostudies-arrayexpress
Project description:Purpose: Mutations in TP53 induce autoantibody immune responses in a subset of cancer patients, which have been proposed as biomarkers for early detection. Here, we investigate the association of p53 specific autoantibodies with multiple tumor subtypes and determine the association with p53 mutation status and epitope specificity. Experimental Design: IgG p53 autoantibodies (p53-AAb), were quantified in 412 serum saples using a programmable ELISA assay from patients with serous ovarian, pancreatic adenocarcinoma, and breast cancer. To determine if patients generated mutation specific autoantibodies we designed a panel of the most relevant 51 p53 point mutant proteins, to be displayed on custom programmable protein microarrays. To determine the epitope specificity we displayed 12 overlapping tiling fragments and 38 N- and C-terminal deletions spanning the length of the wild-type p53 proteins. Results: We detected p53-AAb with sensitivities of 58.8% (ovarian), 22% (pancreatic), 32% (triple negative breast cancer), and 10.2% (HER2+ breast cancer) at 94% specificity. Sera with p53-AAb contained broadly-reactive autoantibodies to 51 displayed p53 mutant proteins, demonstrating a polyclonal response to common epitopes. All p53-AAb displayed broad polyclonal immune response to both continuous and discontinuous epitopes at the N- and C-terminus as well as the DNA binding domain. Conclusion and clinical relevance: In this comprehensive analysis, mutations in tumor p53 induce strong, polyclonal autoantibodies with broadly reactive epitope specificity.
2016-06-01 | GSE77949 | GEO
Project description:Purpose: To compare cell states between control Her2-BBz and JUN-overexpression Her2-BBz human CAR T cells in a mouse model of osteosarcoma. Methods: 8-week old NSG mice were implanted with 1 million 143B osteosarcoma tumor cells intramuscularly in the right leg. 14 days post tumor implantation, mice were infused intravenously with 10 million human CAR+ T cells via tail vein injection. Before T cell transfer, mice were randomized for tumor size and treated with either control Her2-BBz or JUN-overexpressing Her2-BBz CAR T cells. T cells were 70% CAR+ at infusion for both groups. 14 days post T cell treatment (day 28 post tumor engraftment), 6 mice per group were euthanized, solid tumor tissue was collected, mechanically dissociated, and single cell suspensions were labeled with human-CD45 antibody and viability dye. Live hCD45+ tumor-infiltrating lymphocytes were sorted from each tumor and 6 samples were pooled for each group. ~35,000-40,000 sorted live cells (counted post sort) for each group were delivered to the Stanford Functional Genomics Facility for 3' single-cell RNA-sequencing on the 10X Genomics platform. Results: We found that substantially more JUN-overexpressing Her2-BBz CAR T cells were within the G2/M and S phases of the cell cycle than control Her2-BBz CAR T cells, consistent with increased in vivo proliferation of JUN-Her2-BBz CAR T cells. Furthermore, JUN-Her2-BBz CAR T cells also demonstrated a more activated transcriptional program (as measured by IL2RA and CD38), while many exhaustion-associated genes were downregulated (PDCD1, BTLA, TIGIT, CD200, ENTPD1, NR4A2) compared to control Her2-BBz CAR T cells. Finally, a small cluster of cells characterized by high IL7R expression (IL7R+ KLF2+ CD27+ TCF7+ SELL+) was apparent in JUN-overexpressing but not in control Her2-BBz CAR T cells, consistent with maintenance of a memory-like population capable of self-renewal. Conclusions: This study provides insights into cell states that could explain the improved efficacy of JUN-overexpression Her2-BBz CAR T cells compared to control Her2-BBz CAR T cells in a mouse model of osteosarcoma.
2019-10-01 | GSE136805 | GEO
Project description:Human CD8+ T cells were transduced with lentivirus encoding for HER2-CAR-2A-GFP or HER2-CAR-2A-BATF3. T cells were either only stimulated once after thawing (acute stimulation) or repeatedly stimulated with HER2+ SKBR3 cells at a 1:2 effector to target (E:T) ratio every 3 days (chronic stimulation).
2023-05-24 | GSE218987 | GEO
Project description:The autoantibodies in serum (IgG antibody labeled with Cy3 and IgM antibody labeled with Cy5) were quantified by serum incubation human protein microarray, and the data of normal people and lung cancer patients were compared to find the predictive markers of autoantibodies in lung cancer
2024-03-02 | GSE168198 | GEO
Project description:In this study, we compared the metabolic effects of TCPOBOP using lipidomic, transcriptomic, and proteomic analyzes in wild-type and humanized CAR-PXR-CYP3A4/3A7 mice. In the humanized mouse model, human CAR retains its constitutive activity in metabolism regulation; however, it is not significantly activated by TCPOBOB. TCPOBOP elevated serum and liver levels of triglycerides and promoted hepatocyte hypertrophy in humanized CAR mice. Hepatic lipidomic analysis revealed a significant accumulation of triglycerides and downregulation of its metabolites in humanized CAR mice. RNA-seq analysis has shown gene expression changes mainly involved in lipid metabolic processes and in ppar, leptine, thyroid, and circadian clock pathways. In summary, we identify TCPOBOP as a lipid metabolism disruptor in humanized CAR mice
2022-01-31 | GSE186654 | GEO
Project description:T cell exhaustion and metabolic dysfunction induced by chronic antigen stimulation within the tumor microenvironment represent formidable obstacles in CAR T cell therapy for solid tumors. Previously, we developed a method to convert effector/exhausted CAR T cells that emerge from repeated antigen stimulation into stem cell memory-like CAR T (termed CAR-iTSCM) cells. These CAR-iTSCM cells exhibit expression of early memory markers and enhanced mitochondrial metabolism after quiescence under culture conditions containing IL-7, CXCL12, and the NOTCH-ligand. However, we noticed that this strategy was effective for CD19 CAR used for blood cancers, but not for HER2 CAR commonly used to treat solid tumors, due to tonic CAR signals. In this study, we developed a new culture condition for CAR iTSCM cells suitable for HER2 CAR and elucidated the mechanism of induction of stemness and mitochondrial fitness. We found that short-term resting condition with IL-7, CXCL12, and pan-tyrosine kinase inhibitor, Dasatinib can induce stem-like CAR T cells at the epigenetic level and enhance mitochondrial metabolism. We identified FOXO1 as a critical regulator in the process of epigenetic and metabolic reprogramming, and anti-tumor activity. We found that overexpression of FOXO1 leads to enhanced mitochondrial metabolism, efficient CAR T cell expansion, and potent anti-tumor effects through epigenetic modifications. These findings suggest that regulating the transcriptional activity of FOXO1 is a promising strategy for engineering effective CAR T cells for treating solid tumors. In this analysis, we aimed to investigate the effects of FOXO1WT overexpression on the transcriptomic profiles in 4-1BB-based HER2 CD8+ CAR T cells which exhibit tonic signals-induced exhaustion hallmarks.
2023-11-21 | GSE247471 | GEO