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Hepatic Artery Transfusion of NKG2D CAR-T Cells to Treat Patients with Previously Treated Liver Metastatic Colorectal Cancer: a Prospective, Multicenter Clinical Trial

ABSTRACT: Interventions: Group 1:CAR-T infusion;Group 2:CAR-T infusion;Group 3:CAR-T infusion Primary outcome(s): Adverse events;Anti-tumor response Study Design: Single arm

DISEASE(S): Colorectal Liver Metastases

PROVIDER: 2707769 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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NKG2D CAR-T Cells to Treat Patients With Previously Treated Liver Metastatic Colorectal Cancer

Project description:Evaluate the clinical safety and feasibility of NKG2D CAR-T administrated by hepatic artery transfusion for patients with previously treated liver metastatic colorectal cancer.

| 2405312 | ecrin-mdr-crc

Single-cell transcriptomic sequencing of BCMA CAR-T cells during CAR-T therapy in refractory primary plasma cell leukemia

Project description:Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the clinical treatment of hematological malignancies due to the prominent anti-tumor effects. B-cell maturation antigen (BCMA) CAR-T cells have demonstrated promising effects in patients with relapsed/refractory multiple myeloma. However, the dynamics of CAR-T cell proliferation and cytotoxicity in a patient remains largely unexplored. Single-cell RNA sequencing samples were collected at three phases: CAR-T products before infusion, CAR-T on day 8 after infusion, and CAR-T on day 15 after infusion. After obtaining the PBMCs for each phase, CAR-T and endogenous T cells were collected by fluorescence-activated cell sorting with anti-Mouse IgG Biotin, FITC Streptavidin, and anti-human CD3 APC.

2020-10-01 | GSE151310 | GEO

CAR-T Hepatic Artery Infusions or Pancreatic Venous Infusions for CEA-Expressing Liver Metastases or Pancreas Cancer

Project description:This is an open label, fixed dose, phase Ib trial of anti-CEA CAR-T cell infusions delivered via the hepatic artery or splenic vein using the Surefire Infusion System (SIS) for patients with CEA-expressing liver metastases or pancreas cancer.

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CAR-T Hepatic Artery Infusions and Sir-Spheres for Liver Metastases

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Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission

Project description:Despite a high response rate in chimeric antigen receptor (CAR) T therapy for acute lymphocytic leukemia (ALL), approximately 50% of patients relapse within the first year, representing an urgent question to address in the next stage of cellular immunotherapy. To investigate the molecular determinants of ultra-long CAR T persistence, we obtained single-cell multi-omics sequencing data from 695,819 pre-infusion CAR T cells at the basal level or upon CAR-specific stimulation from 82 pediatric ALL patients enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type-2 functionality in CAR T infusion products was significantly associated with patients maintaining a median B-cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions unveiled that type-2 cells regulate a distinct dysfunctional population, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing functional fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of post-infusion sera revealed a higher level of circulating type-2 cytokines in 5-year or 8-year relapse-free responders. In a leukemic mouse model, type-2 high CAR T products demonstrated superior expansion and antitumor activity particularly upon leukemia rechallenge. Restoring antitumor efficacy in type-2 low CAR T cells was attainable by enhancing their type-2 functionality, either through incorporating IL-4 into the manufacturing process or priming manufactured CAR T products with IL-4 prior to infusion. Our findings provide key insights into the mediators of CAR T longevity and suggest potential therapeutic strategies to sustain long-term remission by boosting type-2 functionality in CAR T cells.

2024-05-27 | GSE262072 | GEO

Disruption of SUV39H1-mediated H3K9 methylation sustains CAR T cell function [scRNA/CITE-seq]

Project description:Single cell gene expression profile of WT and SUV39H1-edited CAR T cells at pre-infusion (Day 0), day 9 and day 16 post infusion in tumor (NALM6) bearing NSG mice

2023-11-03 | GSE246960 | GEO

NKG2D CAR-T(KD-025) in the Treatment of Relapsed or Refractory NKG2DL+ Tumors

Project description:This is a Phase 1, single-arm, single-center, open-label study to evaluate the safety and effectiveness of NKG2D-based CAR-T cells infusion in the treatment of relapsed/refractory NKG2DL+ solid tumors.

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Clonal kinetics and single cell transcriptional profiling of adoptively transferred CD19-specific CD8+ CAR-T cells in adults with B cell malignancies

Project description:Lymphodepletion chemotherapy followed by infusion of T cells modified to express a CD19-targeting chimeric antigen receptor (CAR) has produced remarkable anti-tumor responses in patients with B cell malignancies. However, little is known about the clonal composition and transcriptional heterogeneity of CAR-T cells in the infusion products (IP) and clonal kinetics after adoptive transfer. We performed single-cell RNA sequencing (scRNA-seq) on CD8+ CAR-T cells isolated from the IP and the blood of patients treated on a phase 1 clinical trial (NCT01865617) with lymphodepletion chemotherapy and a defined formulation of CD4+ and CD8+ CD19-specific CAR-T cells. Infused CD8+ CAR-T cells displayed transcriptional heterogeneity which declined after adoptive transfer, coincident with early expression of genes associated with activation. We identified four transcriptionally distinct CAR-T cell subsets in the IP and found that these subsets differed in their contributions to the CAR-T cell population detected in blood after infusion. Better understanding of the kinetics of clonal expansion of CAR-T cells after adoptive transfer may provide insight into strategies to improve CAR-T cell immunotherapy.

2019-11-22 | GSE125881 | GEO

Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL). While a majority of patients will achieve a complete response following a single infusion of CD19 CAR T cells, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterised by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumour burden CRS is often responsive to IL-6 receptor blockade, but may require intensive life support and further treatment with high dose corticosteroids to prevent potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. We report here a murine model of CRS that develops within 2-3 days of CAR T cell infusion, may be lethal and is responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines but by IL-6, interleukin-1 (IL-1) and Nitric Oxide (NO) produced by recipient macrophages. This CRS mechanism enables novel therapeutic interventions.

2018-05-28 | GSE111236 | GEO

NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells

Project description:Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), that are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation. In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored how soluble NKG2DL affected NKG2D-CAR T cells´ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells. In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by soluble NKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells. The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.

2023-03-29 | GSE228528 | GEO

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