“Autolus’ growing set of programming modules addresses a range of inhibitory factors within the highly complex and dynamic solid tumor microenvironment. This presentation demonstrates the utility of three modules added to the clinically active and validated AUTO6 GD-2 targeting CAR that not only improve CAR T persistence but also combat the immunosuppressive environment,” said Dr. Christian Itin, chairman and chief executive officer of Autolus. “Based on these encouraging pre-clinical results, which demonstrate the activity of AUTO6NG, we plan on initiating a clinical study in patients with GD2 positive tumors including refractory/relapsed neuroblastoma in the second half of next year.”
AUTO6NG: Next generation GD2-targeting CAR T-cell therapy with improved persistence and insensitivity to TGFBeta and checkpoint inhibition for relapsed/refractory neuroblastoma, Achkova, D., et al. (Abstract number P146, poster presentation, 7:00 am – 8:30 pm Eastern Time on Saturday, November 9)
AUTO6 had previously shown clinical responses without inducing neurotoxicity in pediatric patients with r/r neuroblastoma (Straathof et al., AACR 2018). Building on AUTO6, additional programming modules were introduced forming AUTO6NG to help the CAR T cells persist in and withstand the hostile tumor microenvironment. AUTO6NG is a GD2-targeted CAR T transduced with modules encoding either an IL7 chimeric cytokine receptor (IL7R_CCR) to increase persistence, or a dominant negative TGFβRII (dnTGFbRII) protein to block inhibitor signals from TGFβ and a truncated SHP2 (dSHP2) protein designed to block inhibitor signals from PD1. Both single and dual transduced CAR T cells were evaluated in vitro for anti-tumor activity, cytokine secretion, T cell proliferation, survival and resistance to immunosuppressive pathways. The addition of IL7R_CCR, dnTGFbRII and dSHP2 modules to the AUTO6NG product augment its functions by extending T-cell persistence and rendering modified T-cells resistant to TGFβ- and PD1/PDL1-driven immune inhibition in vitro. Additionally, intravenous delivery of AUTO6NG in NSG mice with established tumor burden exhibited potent anti-tumor activity and extended survival, whereas AUTO6 showed no activity in that model.
AUTO6NG is a next generation programmed T cell product candidate in pre-clinical development. AUTO6NG builds on preliminary proof of concept data from AUTO6, a CAR in clinical development for the treatment of neuroblastoma, which can target GD2-expressing cancers with a chimeric antigen receptor (CAR). AUTO6NG incorporates additional cell programming modules to augment its functions by extending persistence and rendering modified T-cells resistant to immune inhibition. With the enhanced properties of AUTO6NG, it may be suitable for the treatment of GD2-expressing solid tumors, including neuroblastoma, osteosarcoma, melanoma, small cell lung cancer, and soft tissue sarcoma.