Ontology highlight
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PROVIDER: PRJNA1056257 | ENA |
REPOSITORIES: ENA
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Project description:Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to enhance efficacy and universally improve patient outcomes. IL-15 and IL-21 are common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T-cells and other lymphocytes. We found that self-delivery of these cytokines by CAR or TCR T-cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T-cells. Across different preclinical murine solid tumor models, we observe enhanced regression with each individual cytokine but the greatest anti-tumor efficacy when T-cells are armored with both. Thus, the co-expression of membrane-tethered IL-15 and IL-21 represents a technology to enhance the resilience and function of engineered T-cells against solid tumors and could be applicable to multiple therapy platforms and diseases.
2023-08-29 | GSE229651 | GEO
Project description:Interleukin-15 (IL15) enhances the antitumor properties of CAR T cells in preclinical solid tumor models but its effects on CAR T cells in humans are not known. Here, we report the first-in-human evaluation of IL15 co-expression in CAR T cells in two cohorts of a total of 24 patients with glypican-3 (GPC3) expressing solid neoplasms. In cohort 1, GPC3-CAR T cells were safe, no objective antitumor responses were detected. In cohort 2, co-expression of IL15 in GPC3-CAR T cells was associated with increased peak expansion in blood and measurable antitumor responses. Cytokine release syndrome was controlled with immunomodulation or with the inducible caspase 9 safety switch. Single cell transcriptomic analyses identified gene expression of tumor infiltrating CAR T cells associated with antitumor responses.
2024-05-01 | GSE253352 | GEO
Project description:This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article:
"Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept"
Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García
Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703
Comment:
This is the second mathematical model, derived from equations 3 to 6, used in the paper.
Reproduction of Figure 5b was achieved by setting alpha_1 = 0.183, in substitution for alpha_1 = 0.2 as quoted in the article.
Abstract:
Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
2024-09-02 | BIOMD0000001014 | BioModels
Project description:This model of the use of chimeric antigen receptor (CAR)-T cell therapy in the treatment of solid tumours is described in the article:
"Dual-Target CAR-Ts with On- and Off-Tumour Activity May Override Immune Suppression in Solid Cancers: A Mathematical Proof of Concept"
Odelaisy León-Triana, Antonio Pérez-Martínez, Manuel Ramírez-Orellana and Víctor M. Pérez-García
Cancers 2021, 13, 703.; doi: 10.3390/cancers13040703
Comment:
This is the first mathematical model, derived from equations 1 and 2, used in the paper.
Reproduction of Fig. 5a was achieved by setting alpha_1 = 0.04, different to the value quoted in the article caption for Fig. 5.
Abstract:
Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments.
2024-09-02 | BIOMD0000001013 | BioModels
Project description:Compare the gene expression profile among armored IL-18 secreting CAR T cells and second-generation CAR T cells
2017-04-03 | GSE97343 | GEO
Project description:Compare the gene expression profile among armored IL-12 secreting CAR T cells and second-generation CAR T cells and TAMs recovered from both groups
2017-07-24 | GSE97665 | GEO
Project description:Despite remarkable progress in B cell malignancies, T cells expressing chimeric antigen receptors (CARs) remain ineffective in solid tumors in part because T cells do not traffic effectively to or survive in tumor tissues. We engineered Vα24-invariant natural killer T cells (NKTs), which intrinsically home to tumor sites, to co-express a GD2-specific CAR with interleukin (IL)15 and evaluated their therapeutic efficacy in children with relapsed/resistant neuroblastoma (NB)(NCT03294954). The first three patients received a single infusion of 3x10e6 autologous CAR-NKTs per square meter of body surface area and tolerated the treatment well. CAR-NKTs expanded in vivo, localized to the tumor, and in one patient induced a near-complete regression of bone metastatic lesions.
2020-08-10 | GSE154037 | GEO
Project description:Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen-presentation pathway, making them a potential “off-the-shelf” cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3-CAR-modified Vδ1T cells in treating solid tumors. Co-expression of interleukin-2 with the B7-H3-CAR led to durable anti-tumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells.Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors.
2024-08-22 | GSE275242 | GEO
Project description:Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable success in the treatment of hematopoietic cancers, but resistance is common, and efficacy is limited in solid tumors. We demonstrate that CAR T-cells autonomously propagate epigenetically-programmed type I interferon signaling through chronic stimulation or antigen-independent tonic activation, which progressively hampers antitumor effector function. EGR2 transcriptional regulator knockoutnot only blocks this type I interferon-mediated inhibitory program, but also independently expands early memory CAR T-cells with improved efficacy against liquid and solid tumors. The protective effect of EGR2 deletion in CAR T-cells against chronic antigen-induced dysfunction can be overridden by interferon-β exposure, suggesting that EGR2 ablation suppresses CAR T-cell dysfunction through inhibition of type I interferon signaling. Finally, enrichment of an EGR2 gene signature is a clinical biomarker for type I interferon-associated CAR T-cell failure and shorter overall patient survival. These findings conceptually connect prolonged CAR T-cell activation with deleterious immunoinflammatory signaling and point to an EGR2-type I interferon axis as a therapeutically amenable biologic system.
2023-02-20 | GSE224192 | GEO
Project description:Vα24-invariant natural killer T cells (NKTs) have antitumor properties that can be enhanced by transgenic expression of tumor-specific receptors. Here, we report the results of the first-in-human clinical evaluation of autologous NKTs co-expressing a GD2-specific chimeric antigen receptor with interleukin (IL)15 (GD2-CAR.15) in 12 children with neuroblastoma (NB) treated on four dose levels (NCT03294954). Objectives included assessing safety, antitumor activity, and immune response. No dose-limiting toxicities occurred, and one patient had grade 2 cytokine release syndrome resolved by tocilizumab. The overall response rate was 25% (3/12) and disease control rate was 58% (7/12) including four patients with stable disease, two partial responses, and one complete response. CD62L+ NKT frequency in infused products correlated with CAR-NKT expansion in patients and was higher in responders than non-responders (71% vs 35.3%, p=0.002). Singe-cell RNA sequencing analysis identified B cell translocation gene 1 (BTG1) as one of the top upregulated genes in GD2-CAR.15-NKTs after in vitro serial tumor challenge. Genetic gain- and loss-of-function experiments revealed that BTG1 is a key driver of hyporesponsiveness in exhausted NKT and T cells. Crucially, NKTs co-expressing GD2-CAR.15 and BTG1-specific shRNA eradicated metastatic NB in mice. These results indicate that CAR-NKTs are safe, produce objective responses in NB patients, and that targeting BTG1 can enhance their therapeutic potency.
2023-04-19 | GSE223071 | GEO