Potentiating adoptive cell therapy using synthetic IL-9 receptors

• DOI: 10.1038/s41586-022-04801-2
• Publication Date: 2022-06-08T16:03:57Z
• Authors: Anusha Kalbasi; Mikko Siurala; Leon L. Su; Mito Tariveranmos...; Lora K. Picton; Pranali Ravikumar; Peng Li; Jian-Xin Lin; Helena Escuin-Ord...; Tong Da; Sarah V. Kremer; Amy L. Sun; Sofia Castelli; Sangya Agarwal; John Scholler; Decheng Song; Philipp C. Rommel; Enrico Radaelli; Regina M. Young; Warren J. Leonard; Antoni Ribas; Carl H. June; K. Christopher Ga...
• Keywords: Adoptive Cell Transfer

Abstract Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in treatment of solid tumours, including need for conditioning chemotherapy 1,2 . Here we designed chimeric receptors have an orthogonal IL-2 extracellular domain (ECD) fused intracellular (ICD) common γ-chain (γ c ) cytokines IL-4, IL-7, IL-9 and IL-21 such cytokine elicits corresponding γ signal. Of these, signal through IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by concomitant activation STAT1, STAT3 STAT5 assume characteristics stem cell memory effector cells. Compared o2R cells, o9R superior anti-tumour efficacy two recalcitrant syngeneic mouse tumour models melanoma pancreatic cancer effective even absence lymphodepletion. Therefore, repurposing IL-9R using a receptor, gain functions, this results improved activity hard-to-treat tumours.