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Ref Type | Journal Article | ||||||||||||
PMID | (30617136) | ||||||||||||
Authors | Chen Y, Sun C, Landoni E, Metelitsa L, Dotti G, Savoldo B | ||||||||||||
Title | Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15. | ||||||||||||
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Abstract Text | A delay in encountering the cognate antigen while in the circulation, and the suboptimal costimulation received at the tumor site are key reasons for the limited activity of chimeric antigen receptor-redirected T cells (CAR-T) in solid tumors. We have explored the benefits of incorporating the IL15 cytokine within the CAR cassette to provide both a survival signal before antigen encounter, and an additional cytokine signaling at the tumor site using a neuroblastoma tumor model.We optimized the construct for the CAR specific for the NB-antigen GD2 without (GD2.CAR) or with IL15 (GD2.CAR.15). We then compared the expansion, phenotype, and antitumor activity of T cells transduced with these constructs against an array of neuroblastoma cell lines in vitro and in vivo using a xenogeneic metastatic model of neuroblastoma.We observed that optimized GD2.CAR.15-Ts have reduced expression of the PD-1 receptor, are enriched in stem cell-like cells, and have superior antitumor activity upon repetitive tumor exposures in vitro and in vivo as compared with GD2.CAR-Ts. Tumor rechallenge experiments in vivo further highlighted the role of IL15 in promoting enhanced CAR-T antitumor activity and survival, both in the peripheral blood and tissues. Finally, the inclusion of the inducible caspase-9 gene (iC9) safety switch warranted effective on demand elimination of the engineered GD2.CAR.15-Ts.Our results guide new therapeutic options for GD2.CAR-Ts in patients with neuroblastoma, and CAR-T development for a broad range of solid tumors. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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iC9.GD2.CAR.IL-15 T-cells | iC9.GD2.CAR.IL-15 T-cells | 0 | 2 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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iC9.GD2.CAR.IL-15 T-cells | iC9.GD2.CAR.IL-15 T-cells comprise T-lymphocytes engineered to express a chimeric antigen receptor (CAR) that targets the disialoganglioside GD2 linked to CD28 and CD3zeta domains, as well as IL-15, and inducible caspase-9, which potentially induces cytotoxicity against tumor cells expressing GD2 and inhibits tumor growth (PMID: 30617136). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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