Eighteen-year survival after GD2-directed Chimeric Antigen Receptor-Modified Immune Effector Cell Treatment for Neuroblastoma
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ABSTRACT:
PROVIDER: PRJNA1198629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31724800.fastq.gz | Fastqsanger.gz | |||
| SRR31724801.fastq.gz | Fastqsanger.gz | |||
| SRR31724802.fastq.gz | Fastqsanger.gz | |||
| SRR31724767.fastq.gz | Fastqsanger.gz | |||
| SRR31724768.fastq.gz | Fastqsanger.gz |
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Project description:We report long-term outcomes up to 18 years of a clinical trial treating children with neuroblastoma with EBV-specific T lymphocytes and CD3-activated T cells – each expressing chimeric antigen receptors (CAR) targeting GD2 but without an embedded costimulatory sequence (1st generation CARs). These CARs incorporated barcoded sequences to track each infused population. Of 11 patients with active disease at infusion, three patients achieved a complete response that was sustained in 2, one for 8 years until lost to follow up and one for 18+ years. Of eight patients with no evidence of disease at time of CAR-T administration, five are disease-free at their last follow-up between 10-15 years post-infusion. Intermittent low levels of transgene were detected during the follow up period with significantly greater persistence in those who were long-term survivors. In conclusion, despite using first-generation vectors that are nowadays no longer employed because of the lack of costimulatory domains, patients with relapsed/refractory neuroblastoma achieved long-term disease control after receiving GD2 CAR-T cell therapy including one patient now in remission of relapsed disease for >18 years.
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Project description:We FACS sorted Ras-transformed human mammary epithelial cells (HMLER cells) into GD2+ and GD2- as well as CD44high/CD24low and CD44low/Cd24highcells and comapred the four different population by array. We FACS sorted Ras-transformed human mammary epithelial cells (HMLER cells) into GD2+ and GD2- as well as CD44high/CD24low and CD44low/Cd24highcells and comapred the four different population by array.
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Project description:We showed that iPSC-derived GD2-CART therapy for SCLC was more effective than peripheral blood-derived GD2-CART. Here, we investigated the molecular difference between iPSC-derived GD2-CARTs and peripheral blood-derived GD2-CARTs.
2023-10-25 | GSE245955 | GEO
Project description:Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system (CNS) tumors that occur most commonly in children and young adults1. Average life expectancy is ten months from diagnosis, and 5-year survival is less than 1%2. Palliative radiotherapy is the only established treatment3, and neither cytotoxic nor targeted pharmacological approaches have demonstrated anti-tumor responses or improved prognosis to date3,4. We previously discovered that the disialoganglioside GD2 is highly and uniformly expressed on H3K27M+ DMG cells and demonstrated that intravenously (IV) administered GD2.4-1BB.z chimeric antigen receptor (CAR) T-cells eradicated established DMGs in patient-derived orthotopic murine models5, thereby providing the rationale for a first-in-human/first-in-child Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced inflammation and edema of the brainstem can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, a number of neurocritical care precautions were incorporated in the clinical trial design and management plan. Here we present the clinical experience from the first four patients with H3K27M+ DMG treated with GD2-CAR T-cells at dose level 1 (DL1; 1e6 GD2-CAR T-cells/kg administered IV). Patients who exhibited clinical benefit were eligible for subsequent administrations of GD2-CAR T-cells. Given preclinical evidence for increased CAR T-cell potency6, and the potential for diminished immunogenicity with locoregional administration, second doses were administered intracerebroventricularly (ICV) through an Ommaya catheter to three patients. As predicted from preclinical models, toxicity was largely related to the neuroanatomical location of the tumors and was reversible with intensive supportive care. Although GD2 is expressed at low levels in normal neural tissue, no evidence of on-target, off-tumor toxicity was observed. Three of four patients exhibited clinical and radiographic improvement, underscoring the promise of this approach for H3K27M+ DMG therapy. Correlative studies of serum and CSF revealed marked proinflammatory cytokine production following GD2 CAR T cell administration and single cell transcriptomic analysis of 65,598 single cells from CAR T cell products and patient CSF has begun to reveal differences that correlate with the heterogeneity between subjects and routes of administration.
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Project description:The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on a phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine IL15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). Twelve previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. The use of aAPCs instead of PBMCs for CAR-NKT restimulation induced a hyperproliferative state associated with a distinct gene expression profile that likely contributed to an explosive lymphocyte expansion event and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products.
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Project description:Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL), known for its poor prognosis and association with Epstein-Barr virus, has a new development with the establishment of the ENKL-J1 cell line. Derived from a patient's bone marrow, ENKL-J1 cells express the ganglioside GD2, making them targets for GD2-directed chimeric antigen receptor T cells. This discovery positions GD2 as a potential therapeutic target. Genetic analysis of ENKL-J1 revealed variants in TP53 and TET2. Single-cell RNA sequencing indicated high expression of genes in key oncogenic pathways such as JAK-STAT, NF-κB, and MAPK, along with genes linked to multidrug resistance, tumor suppression, and anti-apoptosis. In vitro, molecular targeting agents like eprenetapopt, tazemetostat, and vorinostat effectively induced apoptosis in these cells, with GD2-directed T cells also showing cytotoxicity in vivo. The ENKL-J1 cell line, therefore, provides valuable insights for developing treatments for ENKL, especially in advanced stages.
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Project description:We FACS sorted Ras-transformed human mammary epithelial cells (HMLER cells) into GD2+ and GD2- as well as CD44high/CD24low and CD44low/Cd24highcells and comapred the four different population by array.
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Project description:In this work, we compared the expression profiles of Anti-GD2- transduced T-cells with Anti-GD2-transduced T-cells co-cultured with SK-Mel-37.
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Project description:The tumor-associated glycosphingolipid ganglioside GD2 presents an attractive target for cancer immunotherapy. This molecule is abundant on different types of cancer cells and is characterized by restricted expression on healthy cells. Tumors exhibit heterogeneity in the expression level of GD2 and, therefore, development of methods for determination of the GD2-positive tumor phenotype for the pertinent application of targeted therapies is required. In this work, we have developed a gene expression-based classifier for the prediction of the GD2-positive tumor phenotype. We analyze RNA-seq data from GD2-positive and GD2-negative cell lines of different tumor types as well as neuroblastoma biopsy material for gene expression levels of enzymes that participate in ganglioside biosynthesis and determine the role of gene expression of these enzymes in the formation of the GD2-positive tumor phenotype. We also apply gene expression patterns known from literature to our data and use large public RNA-seq datasets to identify novel gene expression patterns associated with GD2 expression to validate the findings in our data. The results of the study may be used for the development of a gene signature which separates GD2-positive from GD2-negative tumors and for prediction of the GD2 phenotype in clinical specimens from cancer patients, and thus be used as a companion diagnostic for anti-GD2 therapy.
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