Clinical study of CAr-T cell therapy foR advanced colorectal cancEr (iCARE)
Ontology highlight
ABSTRACT:
DISEASE(S): Advanced Colorectal Cancer
PROVIDER: 2704980 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:This mathematical model of T cell-tumour interactions considering the roles of T cell competition and stochastic extinction events in CAR T cell therapy is described by the publication:
Kimmel GJ, Locke FL, Altrock PM. "The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy." Proc Biol Sci. 2021 Mar 31;288(1947):20210229.
doi: 10.1098/rspb.2021.0229
Comment:
Reproduction of Fig. 2(a) and (b) was simulated by using the fitted model parameter set given in Table 1 of the manuscript's Supplementary Material, however substituting the values of r_N and rho_C for those stated in Table 1 of the publication manuscript, i.e. r_N = 0.17 and rho_C = 0.0251.
Abstract:
Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.
2024-09-02 | BIOMD0000001041 | BioModels
Project description:Interventions: experimental group:CAR-T Cell
Primary outcome(s): objective response rate;safety
Study Design: Single arm
| 34987 | ecrin-mdr-crc
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:The goal of this study was to assess the consequences of RNA delivery via CAR-T cell on endogenous immune cells within the B16 tumor microenvironment. RN7SL1 RNA-producing CAR-T cells are the relevant experimental condition, while control scramble RNA and No RNA 19BBz CAR-T cells are also included.
2021-09-01 | GSE179253 | GEO
Project description:The study aimed to elucidate the transcriptional changes introduced by genetic engineering of CAR T cells to stably express the homeostatic chemokine receptor CCR7. In vitro killing assays hinted to a higher cytolytic capacity that could be tied to an altered cytoskeletal rearrangement. Human CAR and CAR.CCR7 T cells were generated by retroviral transduction and enriched by FACS at the end of the expansion phase (day 10), either without or with a previous over-night co-culture with target Jeko1 tumor cells that express the CAR target antigen CXCR5. Enriched cells were immediately processed for bulk mRNA Seq
2023-06-30 | E-MTAB-12778 | biostudies-arrayexpress
Project description:Cellular immunotherapy using autologous, genetically modified T cells has delivered remarkable initial response rates in various hematological malignancies, including acute lymphoblastic leukemia (ALL) or lymphoma. Upon treatment with these chimeric antigen receptor (CAR) T cells, approximately 30–40% of patients show long-term remission. There is a growing perception that not only CAR constructs, but also in vitro manufacturing processes may determine therapeutic efficacy. However, little is known about how duration of culture expansion affects molecular and functional features of CAR T cells. A better understanding of molecular signatures, reflecting therapeutic activity of CAR T cells, may help to further optimize the manufacturing process. In this study, we therefore investigated DNAm changes during culture expansion of T cells and CAR T cells during a period of up to three weeks. The results of our current study indicate that culture expansion of CAR T cells leads to DNAm changes that are continuously acquired during culture expansion. Further analysis of culture-associated methylation profiles in CAR T cells from clinical trials support the notion that these chnages are disadvantageous with regards to therapeutic outcome. A shortened cultivation period to avoid dysfunctional methylation programs might be a promising manufacturing strategy to improve therapeutic efficacy of adoptive cell therapies. Our epigenetic signature for culture-associated DNAm may provide a biomarker for quality control of CAR T cell productions and to identify patients at risk for adverse events.
2023-07-20 | GSE220157 | GEO
Project description:Cellular immunotherapy using autologous, genetically modified T cells has delivered remarkable initial response rates in various hematological malignancies, including acute lymphoblastic leukemia (ALL) or lymphoma. Upon treatment with these chimeric antigen receptor (CAR) T cells, approximately 30–40% of patients show long-term remission. There is a growing perception that not only CAR constructs, but also in vitro manufacturing processes may determine therapeutic efficacy. However, little is known about how duration of culture expansion affects molecular and functional features of CAR T cells. A better understanding of molecular signatures, reflecting therapeutic activity of CAR T cells, may help to further optimize the manufacturing process. In this study, we therefore investigated DNAm changes during culture expansion of T cells and CAR T cells during a period of up to three weeks. The results of our current study indicate that culture expansion of CAR T cells leads to DNAm changes that are continuously acquired during culture expansion, which is also reflected on gene expression level. Further analysis of culture-associated methylation profiles in CAR T cells from clinical trials support the notion that these chnages are disadvantageous with regards to therapeutic outcome. A shortened cultivation period to avoid dysfunctional methylation programs might be a promising manufacturing strategy to improve therapeutic efficacy of adoptive cell therapies. Our epigenetic signature for culture-associated DNAm may provide a biomarker for quality control of CAR T cell productions and to identify patients at risk for adverse events.
2023-07-20 | GSE220580 | GEO
Project description:Chimeric antigen receptor (CAR) T cell therapy has proven highly successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrate that antagonizing Inhibitor of Apoptosis Proteins (IAPs) with the clinical smac-mimetic, birinapant, significantly enhanced the anti-tumor activity of CAR T cells in a TNF-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T cell-derived TNF. Importantly, combining CAR T cell therapy with birinapant dramatically reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrate the synergistic potential of combining CAR T cell therapy with smac-mimetics. Taken together, we identify CAR T cell-derived TNF as a potent anti-tumor effector, which can be further harnessed by smac-mimetics.
2019-02-01 | GSE124140 | GEO
Project description:Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionized the treatment of blood cancers. Parsing the genetic underpinnings of T cell precursor quality and subsequent CAR-T efficacy is challenging. RNA-seq informs infused CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasizes effector and metabolism genes. We investigated whether analyses of transcriptionally repressive and permissive histone methylation marks reveal associations with CAR-T potential beyond what is seen by transcriptomic analysis. We assessed human CD8+ T cell naïve, central and effector memory subsets that form the substrate of CAR-T cell products, and CAR-T cells derived from these subsets. We extended these observations into the clinic, by examining CAR-T products from a clinical trial of lymphoma patients (NCT01865617). We report that histone marks provide a rich dataset for identification of genes not apparent by conventional transcriptomics. Histone marks improved identification of T cell subsets, CAR-T manufactured from these subsets, and CAR-T manufactured from central memory cells from healthy donors and patients. Using this discriminative approach, we controlled for clinical factors and identified a factor, KLF7, associated with CAR-T cell expansion in patients. Epigenomic methods are an orthogonal, robust and wide-reaching approach for the assessment of T cell immunotherapeutic quality.
2024-08-04 | GSE254808 | GEO
Project description:Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionized the treatment of blood cancers. Parsing the genetic underpinnings of T cell precursor quality and subsequent CAR-T efficacy is challenging. RNA-seq informs infused CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasizes effector and metabolism genes. We investigated whether analyses of transcriptionally repressive and permissive histone methylation marks reveal associations with CAR-T potential beyond what is seen by transcriptomic analysis. We assessed human CD8+ T cell naïve, central and effector memory subsets that form the substrate of CAR-T cell products, and CAR-T cells derived from these subsets. We extended these observations into the clinic, by examining CAR-T products from a clinical trial of lymphoma patients (NCT01865617). We report that histone marks provide a rich dataset for identification of genes not apparent by conventional transcriptomics. Histone marks improved identification of T cell subsets, CAR-T manufactured from these subsets, and CAR-T manufactured from central memory cells from healthy donors and patients. Using this discriminative approach, we controlled for clinical factors and identified a factor, KLF7, associated with CAR-T cell expansion in patients. Epigenomic methods are an orthogonal, robust and wide-reaching approach for the assessment of T cell immunotherapeutic quality.
2024-08-04 | GSE254807 | GEO