A Clinical Trial of TAA06 Injection in Advanced Solid Tumors
Ontology highlight
ABSTRACT:
DISEASE(S): Malignant Melanoma, Lung Cancer, Or Colorectal Cancer,Melanoma
PROVIDER: 2400863 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Abstract. The use of large animal spontaneous models of solid cancers, such as dogs with osteosarcoma (OS), can help develop new cancer immunotherapy approaches, including chimeric antigen receptor (CAR) T cells. Therefore, the goal of the present study was to generate canine CAR T cells targeting the B7-H3 (CD276) co-stimulatory molecule overexpressed by several solid cancers, including OS and glioma in both humans and dogs, and to assess their ability to recognize B7-H3 expressed by canine OS cell lines or by canine tumors in xenograft models. A second objective was to determine whether a novel dual CAR that expressed a chemokine receptor together with the B7-H3 CAR improved the activity of the canine CAR T cells. Therefore, in the studies reported here we examined B7-H3 expression by canine OS tumors, evaluated target engagement by canine B7-H3 CAR T cells in vitro, and compared the relative effectiveness of B7-H3 CAR T cells versus B7-H3-CXCR2 dual CAR T cells in canine xenograft models. We found that most canine OS tumors expressed high levels of B7-H3, whereas levels were undetectable on normal dog tissues. In vitro, both B7-H3 CAR T cells demonstrated activation and OS-specific target killing in vitro, but there was significantly greater cytokine production by B7-H3-CXCR2 CAR T cells. In canine OS xenograft models, little antitumor activity was generated by B7-H3 CAR T cells, whereas B7-H3-CXCR2 CAR T cells significantly inhibited tumor growth, inducing complete tumor elimination in most treated mice. These findings indicated therefore that addition of a chemokine receptor could significantly improve the anti-tumor activity of canine B7-H3 CAR T cells, and that evaluation of this new dual CAR construct in dogs with primary or metastatic OS is warranted since such studies could provide a critical and realistic validation of the chemokine receptor concept.
2024-04-03 | GSE247355 | 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:Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR)-T cells in the treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to CAR-T cell therapy resistance in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. Here, we examined the activity of B7-H3 (CD276) directed CAR-T (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and confirmed activity of B7-H3.CAR-T in PDOTS. While B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR-T cells following target cell encounter that led to CAR-T cell dysfunction and limited efficacy against B7-H3 expressing tumors. PD-1 blockade restored CAR-T activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR-T efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR-T activity in monotypic and organotypic tumor spheroids, prevented CAR-T cell dysfunction, and enhanced T cell proliferation. Inhibition or deletion of TBK1 also enhanced sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR-T cells using PDOTS and suggest that targeting TBK1 is a novel strategy to enhance CAR-T efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.
2024-09-24 | GSE277569 | 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:Neuroblastoma (NB) is the most common extra-cranial solid tumor in children and remains deadly in patients with high-risk disease. Single chimeric antigen receptor T-cell therapies (CAR-T) for solid tumor have shown poor efficacy in clinical trials due, in part, to T cell exhaustion and uneven expression of target antigens in tumors. Here, we attempted to target Glypican-2(GPC2) and CD276(B7-H3), both highly but heterogeneously expressed on NB cell surface, to overcome these challenges in single CAR T- therapies. First, to identify optimal binders for CAR T- cell targeting each antigen, we made individual CAR constructs using multiple binders against these antigens and utilized a multimodal approach including simultaneous protein and transcriptome measurement at single cell level to characterize each individual CAR T- cell in a pooled strategy. Combined with cell expansion and cytotoxicity assays, we identified the most effective CAR construct for each target.
2022-03-18 | GSE181437 | GEO
Project description:Chimeric antigen receptor T cells (CAR-T) therapy has not yet been fully explored in solid tumors. Human epidermal growth factor receptor-2(HER2) is widely expressed in cancers. Investigators have developed anti-HER2 CAR-modified T cells and validated the efficiency targeting HER2-positive cancer in preclinical studies. This study is aimed to confirm its adverse effects including cytokine storm response and any other adverse effects. In addition, CAR-T cells persistence, tumor elimination and disease status after treatment will be evaluated.
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Project description:We have employed mRNA microarray expression profiling as a discovery platform to identify genes with the potential to explain how small dose SAHA promoted the cell toxicity of B7-H3 CAR-T cells. B7-H3 CAR-T cells were treated by 0.5μM SAHA for 5 days, and with control samples.
2019-08-06 | GSE135379 | GEO
Project description:Chimeric antigen receptor (CAR)-T cell therapy targeting human CD19 have demonstrated clinical efficacy against B-cell malignancies. However, CAR-T cell therapy's efficacy against solid tumors is limited due to factors like low tumor-associated antigens, infiltration rate, and T cell exhaustion. We have shown that deleting NR4a genes in CAR-T cells prevents T cell exhaustion and improved their therapeutic effects on solid tumors in a mouse model. To further explore this for human, we deleted all three NR4a family factors in CAR-T cells that recognize Epidermal Growth Factor Receptor type 2 (HER2) using the CRISPR/Cas9 system. These modified CAR-T cells (NR4a-TKO CAR-T) exhibited resistance to exhaustion, increased tumor-killing activity, and higher efficacy in tumor regression and survival rate in a human lung carcinoma model in mice. The enhanced therapeutic effects were associated with increased cytokine expression, reduced exhaustion-related gene expression, and improved persistence within tumors. We propose that targeting NR4a could be a promising strategy for developing superior CAR-T cells against solid tumors.
2024-08-28 | GSE241456 | GEO
Project description:The limited efficacy of chimeric antigen receptor (CAR) T-cell therapy for solid tumors necessitates engineering strategies that promote functional persistence in an immunosuppressive environment. Herein, we exploit c-Kit signaling, a physiological pathway associated with stemness in hematopoietic progenitor cells (T cells lose expression of c-Kit during differentiation). CAR T cells with intracellular expression—but no cell-surface receptor expression—of the c-Kit D816V mutation (KITv) have upregulated STAT phosphorylation, antigen-activation-dependent proliferation, CD28- and IL-2–independent and IFN-γ–mediated costimulation, augmenting the cytotoxicity of first-generation CAR T cells. This translates to enhanced survival, including in TGF-β–rich and low-antigen-expressing solid tumor models. KITv CAR T cells have equivalent or better in vivo efficacy than second-generation CAR T cells and are susceptible to tyrosine kinase inhibitors (safety switch). When combined with CD28 costimulation, KITv costimulation functions as a third signal, enhancing efficacy and providing a potent approach to treat solid tumors.
2023-04-24 | GSE229026 | GEO