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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.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 25
Issue 9
Date 2019 05 01
URL
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.

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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