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; K Christopher Garcia

doi:10.1038/s41586-022-04801-2

Potentiating adoptive cell therapy using synthetic IL-9 receptors

Nature. 2022 Jul;607(7918):360-365. doi: 10.1038/s41586-022-04801-2. Epub 2022 Jun 8.

Authors

Anusha Kalbasi^#^{1

2}, Mikko Siurala^#^{3

4}, Leon L Su^#⁵, Mito Tariveranmoshabad⁶, Lora K Picton⁵, Pranali Ravikumar⁴, Peng Li⁷, Jian-Xin Lin⁷, Helena Escuin-Ordinas⁸, Tong Da⁴, Sarah V Kremer⁶, Amy L Sun⁸, Sofia Castelli⁴, Sangya Agarwal⁴, John Scholler⁴, Decheng Song⁴, Philipp C Rommel⁴, Enrico Radaelli⁹, Regina M Young⁴, Warren J Leonard⁷, Antoni Ribas^{10

11}, Carl H June^{12

13}, K Christopher Garcia^{14

15

16

17}

Affiliations

¹ Department of Radiation Oncology, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. anushakalbasi@mednet.ucla.edu.
² Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. anushakalbasi@mednet.ucla.edu.
³ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
⁴ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Department of Radiation Oncology, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁸ Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Penn Vet Comparative Pathology Core, Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. aribas@mednet.ucla.edu.
¹¹ Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. aribas@mednet.ucla.edu.
¹² Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. cjune@upenn.edu.
¹³ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
¹⁴ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. kcgarcia@stanford.edu.
¹⁵ Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.
¹⁶ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.
¹⁷ Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Animals
Cell- and Tissue-Based Therapy* / methods
Immunotherapy, Adoptive* / methods
Interleukin Receptor Common gamma Subunit* / genetics
Interleukin Receptor Common gamma Subunit* / immunology
Interleukins / genetics
Interleukins / immunology
Melanoma / immunology
Mice
Neoplasms* / genetics
Neoplasms* / immunology
Pancreatic Neoplasms / immunology
Receptors, Interleukin-9* / genetics
Receptors, Interleukin-9* / immunology
Recombinant Fusion Proteins* / genetics
Recombinant Fusion Proteins* / immunology
STAT Transcription Factors / metabolism
T-Lymphocytes* / immunology
T-Lymphocytes* / metabolism

Substances

Interleukin Receptor Common gamma Subunit
Interleukins
Receptors, Interleukin-9
Recombinant Fusion Proteins
STAT Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding