Tailoring Treatment in Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2732911 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:CRISPR technologies have begun to revolutionize T cell therapies; however, conventional CRISPR/Cas9 genome-editing tools are limited in their safety, efficacy, and scope. To address these challenges, we developed MEGA (Multiplexed Effector Guide Arrays), a platform for programmable and scalable regulation of the T cell transcriptome using the RNA-guided, RNA-targeting activity of CRISPR/Cas13d. MEGA enables quantitative, reversible, and massively-multiplexed gene knockdown in primary human T cells without targeting or cutting genomic DNA. Applying MEGA to a model of CAR T cell exhaustion, we robustly suppressed inhibitory receptor upregulation and uncovered paired regulators of T cell function through combinatorial CRISPR screening. We additionally implemented druggable regulation of MEGA to control CAR activation in a receptor-independent manner. Lastly, MEGA enabled multiplexed disruption of immunoregulatory metabolic pathways to enhance CAR T cell fitness and anti-tumor activity in vitro and in vivo. MEGA offers a versatile synthetic toolkit for applications in cancer immunotherapy and beyond.
2023-11-06 | GSE246823 | GEO
Project description:This model is based on the publication:
"CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models".
Odelaisy León-Triana, Soukaina Sabir, Gabriel F. Calvo, Juan Belmonte-Beitia, Salvador Chulián, Álvaro Martínez-Rubio, María Rosa, Antonio Pérez-Martínez, Manuel Ramirez-Orellana, Víctor M. Pérez-García
doi: 10.1016/j.cnsns.2020.105570
Comment:
This model is based on equations (4a)-(4c).
Abstract:
Immunotherapies use components of the patient immune system to selectively target can- cer cells. The use of chimeric antigenic receptor (CAR) T cells to treat B-cell malignancies –leukaemias and lymphomas–is one of the most successful examples, with many patients experiencing long-lasting full responses to this therapy. This treatment works by extract- ing the patient’s T cells and transducing them with the CAR, enabling them to recognize and target cells carrying the antigen CD19 + , which is expressed in these haematological cancers. Here we put forward a mathematical model describing the time response of leukaemias to the injection of CAR T cells. The model accounts for mature and progenitor B-cells, leukaemic cells, CAR T cells and side effects by including the main biological processes involved. The model explains the early post-injection dynamics of the different compart- ments and the fact that the number of CAR T cells injected does not critically affect the treatment outcome. An explicit formula is found that gives the maximum CAR T cell ex- pansion in vivo and the severity of side effects. Our mathematical model captures other known features of the response to this immunotherapy. It also predicts that CD19 + cancer relapses could be the result of competition between leukaemic and CAR T cells, analogous to predator-prey dynamics. We discuss this in the light of the available evidence and the possibility of controlling relapses by early re-challenging of the leukaemia cells with stored CAR T cells.
2024-09-02 | BIOMD0000001011 | BioModels
Project description:ALFAOMEGA-RETRÒ will be exploited to retrospectively collect clinical and imaging data and archival samples to be used for validation and correlative studies on markers discovered by cutting-edge translational projects within the AIRC5x1000 program "Insights into the evolving heterogeneity of colorectal cancer (CRC): from mechanism to therapies" (an ongoing multi-institutional research program).
| 2394032 | ecrin-mdr-crc
Project description:This model is based on the publication:
"CAR T cell therapy in B-cell acute lymphoblastic leukaemia: Insights from mathematical models".
Odelaisy León-Triana, Soukaina Sabir, Gabriel F. Calvo, Juan Belmonte-Beitia, Salvador Chulián, Álvaro Martínez-Rubio, María Rosa, Antonio Pérez-Martínez, Manuel Ramirez-Orellana, Víctor M. Pérez-García
doi: 10.1016/j.cnsns.2020.105570
Comment:
This model is based on equations (3a)-(3c) from the paper.
Abstract:
Immunotherapies use components of the patient immune system to selectively target can- cer cells. The use of chimeric antigenic receptor (CAR) T cells to treat B-cell malignancies –leukaemias and lymphomas–is one of the most successful examples, with many patients experiencing long-lasting full responses to this therapy. This treatment works by extract- ing the patient’s T cells and transducing them with the CAR, enabling them to recognize and target cells carrying the antigen CD19 + , which is expressed in these haematological cancers. Here we put forward a mathematical model describing the time response of leukaemias to the injection of CAR T cells. The model accounts for mature and progenitor B-cells, leukaemic cells, CAR T cells and side effects by including the main biological processes involved. The model explains the early post-injection dynamics of the different compart- ments and the fact that the number of CAR T cells injected does not critically affect the treatment outcome. An explicit formula is found that gives the maximum CAR T cell ex- pansion in vivo and the severity of side effects. Our mathematical model captures other known features of the response to this immunotherapy. It also predicts that CD19 + cancer relapses could be the result of competition between leukaemic and CAR T cells, analogous to predator-prey dynamics. We discuss this in the light of the available evidence and the possibility of controlling relapses by early re-challenging of the leukaemia cells with stored CAR T cells.
2024-09-02 | BIOMD0000001012 | BioModels
Project description:Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells, and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knock-in or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression re-shaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together these findings provide a system for identification of GOF immune boosters, and demonstrate PRODH2 as a target to enhance CAR-T efficacy.
2022-02-12 | ST002085 | MetabolomicsWorkbench
Project description:Chimeric antigen receptor (CAR)-T cell-based immunotherapy for cancer and immunological diseases has made great strides, but it still faces multiple hurdles. Finding the right molecular targets to engineer T cells toward a desired function has broad implications for the armamentarium of T cell-centered therapies. Here, we developed a dead-guide RNA (dgRNA)-based CRISPR activation screen in primary CD8+ T cells, and identified gain-of-function (GOF) targets for CAR-T engineering. Targeted knock-in or overexpression of a lead target, PRODH2, enhanced CAR-T-based killing and in vivo efficacy in multiple cancer models. Transcriptomics and metabolomics in CAR-T cells revealed that augmenting PRODH2 expression re-shaped broad and distinct gene expression and metabolic programs. Mitochondrial, metabolic and immunological analyses showed that PRODH2 engineering enhances the metabolic and immune functions of CAR-T cells against cancer. Together these findings provide a system for identification of GOF immune boosters, and demonstrate PRODH2 as a target to enhance CAR-T efficacy.
2022-02-14 | ST002084 | MetabolomicsWorkbench
Project description:Adoptive cell therapy, a subset of cancer immunotherapy, is collection of therapeutic approaches which aim to redirect the immune system by reprogramming patient T-cells to target antigenic molecules differentially and specifically expressed in certain cancers. One promising immunotherapy technique is CAR T-cell therapy, where cancer cells are targeted through the expression a chimeric antigen receptor (CAR), a synthetic trans- membrane receptor that functionally compensates for the T-cell receptor (TCR) but targets a tumor associated antigen on the cancer cell surface. While CAR T-cell therapy is promising with two clinically approved second-generation CARs (Kymriah and Yescarta), few studies have investigated the mechanism of signal propagation in T-cells and no studies have investigated the potential signaling response in the target cells. To gain further insight to CAR-based signaling, we stimulated third generation CD19 CAR-expressing Jurkat T-cells by co-culture with SILAC labeled CD19HI Raji B-cells and used two phosphoenrichment strategies coupled with liquid chromatography-tandem mass spec- trometry (LC-MS/MS) to detect and analyze global phosphorylation changes in both cell populations. Analysis of the phosphopeptides originating from the CD19-CAR T cells revealed an increase in many phosphorylation events necessary for canonical TCR signaling. We also observed for the first time a significant decrease in B-cell receptor- related phosphopeptide abundance in CD19HI Raji B-cells after co-culture with CD19-targetted CAR T-cells.
2022-01-28 | PXD028109 | Pride
Project description:Targeting tumor-specific neoantigens is promising for cancer immunotherapy, yet their ultra-low expression on tumor cells poses significant challenges for T cell therapies. Here, we found that chimeric antigen receptors (CARs) exhibited 10-100 times lower sensitivity compared to T cell receptors (TCRs) when targeting p53R175H common neoantigen. To enhance CAR functionality, we introduce T cell receptor fusion construct (TRuC) and synthetic TCR and antigen receptor (STAR). Our data demonstrate that STAR, which incorporates TCR-mimic antibody fragments and complete TCR signaling machinery, optimally reproduces antigen sensitivity of TCRs. STAR outperforms both CAR and TRuC in redirecting both CD8+ and CD4+ T cells to recognize HLA class I neoantigens. In vitro, human primary T cells engineered with STAR kill multiple cancer cell lines with low neoantigen density better than CAR-T and TRuC-T cells. In tumor mouse models, STAR-T cells outperform CAR-T and TRuC-T cells in controlling neoantigen-low breast cancer and leukemia. Taken together, our findings highlight severe defects in CAR sensitivity and introduce STAR as a more sensitive synthetic receptor, providing a new framework for T cell-based immunotherapy targeting tumors with low neoantigen density.
2024-10-31 | GSE279137 | GEO
Project description:Adoptive transfer of chimeric antigen receptor (CAR)-T cells is expected to become the first line of treatment for multiple malignancies, following the enormous success of anti-CD19 therapies. However, their mechanism of action is not fully understood, and clear guidelines for the design of safe and efficient receptors are missing. We hereby describe a systematic analysis of the CAR “signalosome” in human primary T cells. Two CAR designs were compared: a second-generation (PSCA2) and a third-generation (PSCA3) anti-PSCA CAR. Phosphorylation events triggered by CAR-mediated recognition of target cells were quantified by mass spectrometry.
2019-11-07 | PXD007086 | Pride
Project description:Cytokine release syndrome (CRS) is a strong immune system response that can occur as a result of the reaction of a cellular immunotherapy with malignant cells. While the frequency and management of CRS in CAR T-cell therapy has been well documented, there is emerging interest in pre-emptive treatment to reduce CRS severity and improve overall outcomes. Accordingly, identification of genomic determinants that contribute to cytokine release may lead to the development of targeted therapies to prevent or abrogate the severity of CRS. We examined CD22 CAR T-cells using the Nanostring nCounter platform and found that the expression of the PFKFB4 gene and glycolytic pathway activity were upregulated in CAR T-cells in those who developed CRS compared to those who did not have CRS.
2022-08-03 | GSE200296 | GEO