Potentiating adoptive cell therapy using synthetic IL-9 receptors
Anusha Kalbasi, Mikko Siurala, Leon Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian‐Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah Kremer, Amy 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 García
Abstract
Abstract Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy 1,2 . Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γ c ) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ c cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.