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NKT cells co-expressing a GD2-specific chimeric antigen receptor and IL-15 mediate regression of refractory metastatic neuroblastoma

ABSTRACT: NKT cells co-expressing a GD2-specific chimeric antigen receptor and IL-15 mediate regression of refractory metastatic neuroblastoma

PROVIDER: PRJNA644911 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12174578_1.fastq.gz	Fastqsanger.gz
	SRR12174578_2.fastq.gz	Fastqsanger.gz
	SRR12174579_1.fastq.gz	Fastqsanger.gz
	SRR12174579_2.fastq.gz	Fastqsanger.gz
	SRR12174580_1.fastq.gz	Fastqsanger.gz

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NKT cells co-expressing a GD2-specific chimeric antigen receptor and IL-15 mediate regression of refractory metastatic neuroblastoma

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

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results

Project description:Vα24-invariant natural killer T cells (NKTs) have antitumor properties that can be enhanced by transgenic expression of tumor-specific receptors. Here, we report the results of the first-in-human clinical evaluation of autologous NKTs co-expressing a GD2-specific chimeric antigen receptor with interleukin (IL)15 (GD2-CAR.15) in 12 children with neuroblastoma (NB) treated on four dose levels (NCT03294954). Objectives included assessing safety, antitumor activity, and immune response. No dose-limiting toxicities occurred, and one patient had grade 2 cytokine release syndrome resolved by tocilizumab. The overall response rate was 25% (3/12) and disease control rate was 58% (7/12) including four patients with stable disease, two partial responses, and one complete response. CD62L+ NKT frequency in infused products correlated with CAR-NKT expansion in patients and was higher in responders than non-responders (71% vs 35.3%, p=0.002). Singe-cell RNA sequencing analysis identified B cell translocation gene 1 (BTG1) as one of the top upregulated genes in GD2-CAR.15-NKTs after in vitro serial tumor challenge. Genetic gain- and loss-of-function experiments revealed that BTG1 is a key driver of hyporesponsiveness in exhausted NKT and T cells. Crucially, NKTs co-expressing GD2-CAR.15 and BTG1-specific shRNA eradicated metastatic NB in mice. These results indicate that CAR-NKTs are safe, produce objective responses in NB patients, and that targeting BTG1 can enhance their therapeutic potency.

2023-04-19 | GSE223071 | GEO

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma – a first-in-human phase 1 trial

2023-05-01 | GSE220927 | GEO

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results

Project description:Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results

| PRJNA924798 | ENA

Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma – a first-in-human phase 1 trial

Project description:Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma – a first-in-human phase 1 trial

| PRJNA912089 | ENA

Eighteen-year survival after GD2-directed Chimeric Antigen Receptor-Modified Immune Effector Cell Treatment for Neuroblastoma

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.

2025-01-08 | GSE284343 | GEO

Hyperleukocytosis in a neuroblastoma patient after treatment with natural killer T cells expressing a GD2-specific chimeric antigen receptor and IL15

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.

2025-03-13 | GSE274643 | GEO

Ganglioside GD2 identifies Breast Cancer Stem Cells: Targeting GD3 Synthase Inhibits GD2 Expression and Tumor Growth

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.

2012-04-12 | E-GEOD-36643 | biostudies-arrayexpress

GD2-CART cells and iPSC-derived GD2-CART cells (scRNA-Seq)

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

CRISPR/Cas9 mutagenesis screening identifies PRDM1 as a key regulator of the natural killer T cell central memory program and effector function

Project description:Natural killer T cells (NKTs) are a promising platform for cancer immunotherapy, but few genes involved in regulation of NKT therapeutic activity have been identified. To discover regulators of NKT functional fitness, we developed a CRISPR/Cas9-based mutagenesis screen that employs a guide (g)RNA library targeting 1,118 immune-related genes. Unmodified NKTs and NKTs expressing a GD2-specific chimeric antigen receptor (CAR.NKTs) were transduced with the gRNA library and exposed to CD1d+/GD2- leukemia or CD1d-/GD2+ neuroblastoma cells, respectively, over six challenge cycles in vitro. Quantification of gRNA abundance revealed enrichment of PRDM1-specific gRNAs in both NKTs and CAR.NKTs, a result that was validated through targeted PRDM1 knockout. Transcriptional, phenotypic, and functional analyses demonstrated that CAR.NKTs with PRDM1 knockout undergo central memory-like differentiation and resist exhaustion while downregulating granzyme B and mediating reduced cytotoxicity in vitro and moderate antitumor activity in an in vivo xenogeneic neuroblastoma model. In contrast, shRNA-mediated knockdown of PRDM1 expression preserved CAR.NKT effector function while promoting central memory differentiation, resulting in CAR.NKTs with potent in vivo antitumor activity. Thus, we identified PRDM1 as a regulator of NKT memory differentiation and effector function that can be exploited to improve the efficacy of next-generation NKT-based cancer immunotherapy.

2025-01-10 | GSE261930 | GEO

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