Potentiating adoptive cell therapy using synthetic IL-9 receptors

Anusha Kalbasi (), Mikko Siurala, Leon L. Su, Mito Tariveranmoshabad, Lora K. Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, 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 () and K. Christopher Garcia ()
Additional contact information
Anusha Kalbasi: University of California, Los Angeles
Mikko Siurala: Parker Institute for Cancer Immunotherapy
Leon L. Su: Stanford University School of Medicine
Mito Tariveranmoshabad: University of California, Los Angeles
Lora K. Picton: Stanford University School of Medicine
Pranali Ravikumar: University of Pennsylvania
Peng Li: National Heart, Lung, and Blood Institute, National Institutes of Health
Jian-Xin Lin: National Heart, Lung, and Blood Institute, National Institutes of Health
Helena Escuin-Ordinas: University of California, Los Angeles
Tong Da: University of Pennsylvania
Sarah V. Kremer: University of California, Los Angeles
Amy L. Sun: University of California, Los Angeles
Sofia Castelli: University of Pennsylvania
Sangya Agarwal: University of Pennsylvania
John Scholler: University of Pennsylvania
Decheng Song: University of Pennsylvania
Philipp C. Rommel: University of Pennsylvania
Enrico Radaelli: University of Pennsylvania
Regina M. Young: University of Pennsylvania
Warren J. Leonard: National Heart, Lung, and Blood Institute, National Institutes of Health
Antoni Ribas: Parker Institute for Cancer Immunotherapy
Carl H. June: Parker Institute for Cancer Immunotherapy
K. Christopher Garcia: Parker Institute for Cancer Immunotherapy

Nature, 2022, vol. 607, issue 7918, 360-365

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 chemotherapy1,2. 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 (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc 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.

Date: 2022
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DOI: 10.1038/s41586-022-04801-2

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