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A phase I/II study for the tolerance, safety, cell kinetics and efficiency of immunotherapy in patients With stage III/IV colorectal cancer

ABSTRACT: Interventions: Group 1:CAR-T;Group 2:combined immunotherapy Primary outcome(s): Tumor imaging;Cytokine IL-6;Cytokine TNF-a;CRP;Copy numbers of CART in vivo Study Design: Non randomized control

DISEASE(S): Colorectal Cancer

PROVIDER: 2685830 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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An open-label, uncontrolled, single-arm pilot study to evaluate vascular interventional therapy mediated CEA-targeted chimeric antigen receptor T cells in advanced colorectal cancer

Project description:Interventions: A:CEA-CART Primary outcome(s): cytokines IL-1beta;cytokine IL-2R;cytokine IL-6;cytokine IL-8;cytokine IL-10;cytokine TNF-alpha;copy numbers of CART in vivo;serum CEA;tumor size Study Design: Non randomized control

| 2668568 | ecrin-mdr-crc

Dasatinib enhances anti-tumor efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion

Project description:CD19-targeted Chimeric antigen receptor T cells (CART) cells have shown remarkable promise in various B cell malignancies. Sustained tonic signaling and antigen exposure drives CART cell differentiation and exhaustion, which limits the therapeutic potency and persistence of CART cells and is a major cause of CD19-expressing leukemia relapse after CD19-targeted CART cells treatment in ALL. Here, we systematically screened FDA approved tyrosine kinase inhibitors, and identified dasatinib as the best candidate to prevent or reverse both CD28/CART and 4-1BB/CART cells from differentiation and exhaustion during ex vivo expansion, which enhanced the therapeutic efficacy and in vivo persistence. Using RNA-seq, we identified the differentially expressed genes between dasatinib treated group and Nalm6 stimulated group, and found that memory-associated transcription factors TCF7 and naive/memory-associated cell surface marker CCR7 were upregulated, whereas exhaustion-related regulators (NR4A1, BATF3, ATF4 and FOS) and inhibitory receptors (PD1, LAG3) were down-regulated in dasatinib treated CAR T cells. Moreover, T cell activation associated signaling pathways (T cell receptor, Jak-STAT, MAPK and PI3K-Akt) which were upregulated in Nalm6 stimulated CART cells, showed fundamental downregulation in dasatinib treated CART cells. These findings imply that dasatinib played important roles in CART cell differentiation and exhaustion by inhibition of T cell activation pathways.

2021-06-03 | GSE151774 | GEO

Local radiation enhances systemic CAR T-cell efficacy by augmenting antigen crosspresentation and T-cell infiltration

Project description:Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19+ B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR T-cell manufacturing. To investigate the impact of 1 to 2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low-dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in nonirradiated tumors. Mechanistically, our results validate activation of the cyclic guanosine adenosine synthetase/stimulator of interferon genes pathway, tumor-associated antigen crosspriming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR T-cell therapy, overcoming treatment resistance and improving clinical outcomes in patients with CD19+ hematologic malignancies.

2024-11-13 | GSE281695 | GEO

Antagonism of IAPs enhances CAR T cell efficacy

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

Characteristics of premanufacture CD8+T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma

Project description:In this study, 58 r/r DLBCL patients treated with tandem CD19/CD20 CAR T cells. Twenty-seven patients had durational responses for more than 24 months, and the median PFS was 21.7 months. But 15 patients still did not have an objective response, and 11 patients relapsed within 1 year. The analysis found that CD8+TSCM cells with higher frequency and stronger activation ability in CART products were the key to achieving clinical sustained objective response. Bulk-RNA-seq results confirmed that CD8+CART cells in CR group had higher expression of memory-related genes and transcription factors and lower expression of activation/depletion related genes than those in PD patients. Naive CD8 cells also showed similar differential expression in apheresis. The use of Naive cells as the source cell population for CART preparation could partially improve CART function, but could not completely reverse it. It is suggested that the resistance of DLBCL to tandem CD19/CD20 CAR T cell therapy may be caused by the decreased function and the loss of expression of memory genes of the source Naive T cells.

2023-11-09 | GSE223655 | GEO

mRNA profiling on CD19-directed chimeric antigen receptor T (CART19) cells with and without platelet-poor plasma from untreated chronic lymphocytic leukemia (CLL) patients (CLL-derived extracellular vesicles)

Project description:Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1+ CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.

2021-01-21 | GSE147046 | GEO

Barros2021 - CARTmath, Mathematical Model of CAR-T Immunotherapy in Raji Cell Line

Project description:A mathematical model (CART-math) studying the impact of CAR-T cells therapy on haematological cancer cell lines which in this case is RAJI.

2024-09-02 | BIOMD0000001020 | BioModels

Barros2021 - CARTmath, Mathematical Model of CAR-T Immunotherapy in HDLM-2 cell line

Project description:A mathematical model (CART-math) studying the impact of CAR-T cells therapy on haematological cancer cell line which in this case is HDLM-2.

2024-09-02 | BIOMD0000001019 | BioModels

C-reactive protein promotes bone destruction in human myeloma by stimulating myeloma cell production of osteolytic cytokines via the CD32A-p38MAPK-twist axis

Project description:Bone destruction is a hallmark of human myeloma and affects more than 80% of patients. Although it is well established that myeloma cells mediate bone destruction by activating osteoclasts, the mechanism how myeloma cells are regulated to do so is unknown. Here we show that C-reactive protein (CRP), a protein secreted in elevated amounts by hepatocytes in response to myeloma-derived cytokines, may be responsible for activating myeloma cells to promote osteoclastogenesis and inducing bone destruction in vivo. CRP binds to surface CD32A/FcRIIA, activates p38MAPK-twist pathways, and upregulates the secretion of osteolytic cytokines by myeloma cells. Clinical studies examining the relationship between the levels of serum CRP and the numbers of osteolytic bone lesions in newly diagnosed patients support this conclusion.

2017-09-12 | GSE103697 | GEO

Chaudhury2020 - Lotka-Volterra mathematical model of CAR-T cell and tumour kinetics

Project description:This ordinary differential equation model of the cellular kinetics and pharmacodynamics of CAR-T cell therapy is described in the publication: Chaudhury, A., Zhu, X., Chu, L., Goliaei, A., June, C., Kearns, J. and Stein, A., 2020. Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic‐Pharmacodynamic Modeling Approaches. The Journal of Clinical Pharmacology, 60(S1). DOI: 10.1002/jcph.1691 Comment: This model is based on equations 4-5 from the manuscript. Abstract: Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity.

2024-09-02 | BIOMD0000001024 | BioModels

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