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:Single-cell RNA sequencing of BM resident immune cells of patients undergoing CAR T-cell infusion and their Infusion Product (IP). Data in this study were generated from a patients enrolled in the FT01CARCIK Phase I/IIb clinical trial (NCT03389035) and two patients treated with autologous commercial CAR T cells (tisagenlecleucel). BM samples have been collected before CAR T treatment (pre) and at early time points (1-2 months) after treatment (post). CD45+CD3+ T cells, and CD45+/lowCD3-, encompassing the hematopoietic immune niche of the TME cells, have been separated by flow cytometry-based cell sorting and compared to cells of the corresponding patient’s BM before CAR T-cell treatment at the moment of relapse. In parallel, CAR T-cell infusion products (IP) have been sorted according to the surface CAR expression. Significance: This study highlights the critical role of the tumor microenvironment on CAR T-cell fate and endogenous immunity in B-cell acute lymphoblastic leukemia. We demonstrate that IFN response, hypoxia, and TGF-b signaling lead to general immune suppression, resulting in endogenous T-cell exhaustion and compromising CAR T-cell efficacy
2025-12-31 | E-MTAB-14549 | biostudies-arrayexpress
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:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
2026-05-30 | PXD079073 | Pride
Project description:Relapsed/refractory Non-Hodgkin's lymphoma (R/R NHL) remains a therapeutic challenge despite advances in immune checkpoint inhibitors (ICIs). While chimeric antigen receptor (CAR) T-cell therapy has shown promise in hematologic malignancies, its efficacy in NHL is limited by T-cell exhaustion and tumor microenvironment (TME) immunosuppression. Preclinical studies suggest that low-dose decitabine, a DNA hypomethylating agent, can epigenetically reprogram T cells to enhance cytotoxicity and persistence. This open-label phase 1/2 trial (NCT04697940) enrolled 33 R/R NHL patients (aged 16–73 years) to evaluate the safety and efficacy of decitabine-primed CAR T cells targeting CD19/CD20 (CART19/20). Patients received lymphodepletion followed by escalating doses (0.5–5×10^6 cells/kg) of decitabine-activated CAR T cells. Primary endpoints included dose-limiting toxicities (DLTs) and objective response rate (ORR); secondary endpoints encompassed progression-free survival (PFS) and mechanistic analyses of T-cell dynamics.In the phase 1 cohort (n=18), no severe cytokine release syndrome (CRS) or neurotoxicity was observed, establishing 5×10^6 cells/kg as the recommended phase 2 dose (RP2D). Among 15 evaluable patients in phase 2, the ORR reached 86.7% (13/15), with a complete remission (CR) rate of 60% (9/15). Median PFS was 22.1 months, significantly surpassing historical controls of PD-1 monotherapy (median PFS: 12–15 months). Mechanistic studies revealed that decitabine pretreatment upregulated AP-1 transcription factor JunD in CAR T cells, promoting clonal expansion of progenitor-exhausted CD8+ T cells and enhancing tumor infiltration.
2026-03-05 | GSE295634 | GEO
Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
2026-05-30 | PXD079082 | Pride
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