Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1056257 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR27378603_1.fastq.gz | Fastqsanger.gz | |||
| SRR27378603_2.fastq.gz | Fastqsanger.gz | |||
| SRR27378604_1.fastq.gz | Fastqsanger.gz | |||
| SRR27378604_2.fastq.gz | Fastqsanger.gz |
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Project description:Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimeric antigen receptor (CAR)-T cell therapies applied to solid tumors. Previously, CAR-T cells were armored with immunostimulatory molecules, such as interleukin-12 (IL-12), to overcome this issue, but faced high toxicity. Here, we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of the prostate 1 (STEAP1) is retained within murine prostate tumors. This leads to high intratumoral interferon-γ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumor antigens after CBD-IL-12-armored CAR-T cell treatment. Combination of CBD-IL-12-armored CAR-T cells and immune checkpoint inhibitors eradicated large tumors in an established prostate cancer mouse model. Additionally, human CBD-IL-12-armored CAR-T cells showed potent anti-tumor efficacy in an 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armored CAR-T cells. CBD-fusion to potent payloads of CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumors.
2025-06-25 | GSE300750 | GEO
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 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: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:Chimeric antigen receptor (CAR)-NK therapy has emerged as a highly promising alternative to CAR-T cell therapy, due to its remarkable efficacy and safety in hematological tumors. However, the efficacy of CAR-NK cells currently remains limited in solid tumors. Here, we successfully developed CISH locus-specific integrated CAR-NK cells using a non-viral mini-circular single-stranded DNA (mcssDNA)-based CRISPR/Cas9 targeted genome editing (mcssDNA/CRISPR/Cas9) technology via a single-step electroporation procedure. The developed CISH-knockout (CISH-KO) CAR-NK cells exhibited the enhanced proliferation and cytotoxicity against hepatocellular carcinoma (HCC) compared with conventional lentivirus-transduced CAR-NK (LV-CAR-NK) cells. Single-cell RNA sequencing analysis revealed an important subset of adaptive NK cells that were highly enriched in CISH-KO CAR-NK cells compared to LV-CAR-NK cells and showed the up-regulated JAK/STAT, energy metabolism and activating receptor signaling. Furthermore, non-viral CISH locus-specific integrated IL-15-armored CAR-NK cells were generated and achieved persistent tumor regression and a significant survival advantage in a lung metastatic mouse model of HCC. Collectively, our results demonstrate that non-viral CISH locus-specific integrated CAR-NK cells can be generated by a simplified, single-step manufacturing procedure and achieve potent efficacy against HCC, thus providing an innovative technology for CAR-NK cell therapy against solid tumors.
2025-05-26 | GSE298054 | GEO
Project description:T-cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCKs) are engineered chimeric antigen receptor (CAR) T-cells that constitutively or inducibly release cytokines upon CAR engagement. Their purpose is to enhance the function of effector cells in the immune-suppressive tumor microenvironment (TME) of particularly solid tumors that is often devoid of pro-inflammatory cytokines. We capitalize on the pleiotropic effects of two γc family cytokines, interleukin (IL)-15 and IL-21, and use them synergistically for TRUCK engineering. We demonstrate that TRUCKs with soluble IL-15/IL-21 eradicate CAR T-cell–resistant neuroblastoma, the most common extra-cranial solid tumor of childhood, but are associated with significant toxicities in mice. These toxicities can be delayed when we constitutively tether the cytokines to the surface of T-cells but are abrogated when we engineer CAR T-cells with NFAT-induced membrane-tethered IL-15/IL-21 expression.
2025-06-17 | GSE243349 | GEO
Project description:Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has demonstrated safety and feasibility in clinic; yet, limited efficacy resulted from intrinsic dysfunction and extrinsic depression remains to be addressed. T cells provide a multifaceted complementation to NK cell-mediated response. Here, we designed a novel CD19-targeted CAR-NK armored with secreted interleukin (IL) -15 and CCL21 (15x21 CAR-NK) that are capable of recruiting and cooperating with T cells. These 15x21 CAR-NK cells possess excellent capacities for cytotoxicity, cytokine production, and effector molecule expression in vitro. The cooperation with T cells presents benefits of alleviating mutual exhaustion and boosting the expression of effector molecules/receptors, thus promoting the elimination of tumor cells efficiently. In addition, 15x21 CAR-NK cells were also highly enriched PI3K/AKT/mTOR pathway, associating with downstream pro-survival signaling, anti-apoptosis ability, and mitochondrial fitness. Collectively, our study highlights the intrinsic superiority and extrinsic T-cell cooperative advantages of 15x21 CAR-NK cells, providing a promising strategy for NK-cell based immunotherapy.
2025-04-25 | GSE278506 | GEO
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: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