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|Ref Type||Journal Article|
|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.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2019 05 01|
|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|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|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|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||neuroblastoma||not applicable||iC9.GD2.CAR.IL-15 T-cells||Preclinical - Cell line xenograft||Actionable||In a preclinical study, iC9.GD2.CAR.IL-15 T-cell treatment inhibited tumor growth and improved tumor-free survival in a cell line xenograft model of neuroblastoma expressing the disialoganglioside GD2 (PMID: 30617136).||30617136|