PD-1-cis IL-2R agonism yields better effectors from stem-like CD8(+) T cells

• Type of Material: Article
• Authors: Laura Codarri Deak, Roche Innovation Center Zurich; Valeria Nicolini, Roche Innovation Center Zurich; Masao Hashimoto, Emory University; Maria Karagianni, Roche Innovation Center Zurich; Petra C Schwalie, Roche Innovation Center Basel; Laura Lauener, Roche Innovation Center Zurich; Eleni Maria Varypataki, Roche Innovation Center Zurich; Marine Richard, Roche Innovation Center Zurich; Esther Bommer, Roche Innovation Center Zurich; Johannes Sam, Roche Innovation Center Zurich; Stefanie Joller, Roche Innovation Center Zurich; Mario Perro, Roche Innovation Center Zurich; Floriana Cremasco, Roche Innovation Center Zurich; Leo Kunz, Roche Innovation Center Zurich; Emilio Yanguez, Roche Innovation Center Zurich; Tamara Husser, Roche Innovation Center Zurich; Ramona Schlenker, Roche Innovation Center Zurich; Marisa Mariani, Roche Innovation Center Zurich; Vinko Tosevski, Roche Innovation Center Zurich; Slvia Herter, Roche Innovation Center Zurich; Marina Bacac, Roche Innovation Center Zurich; Inja Waldhauer, Roche Innovation Center Zurich; Sara Colombetti, Roche Innovation Center Zurich; Xavier Gueripel, Roche Innovation Center Zurich; Stephan Wullschleger, Ecole Polytech Fed Lausanne; Melanie Tichet, Ecole Polytech Fed Lausanne; Douglas Hanahan, Ecole Polytech Fed Lausanne; Haydn Kissick, Emory University; Stephane Leclair, Roche Innovation Center Munich; Anne Freimoser-Grundschober, Roche Innovation Center Munich; Stefan Seeber, Roche Innovation Center Munich; Volker Teichgräber, Roche Innovation Center Basel; Rafi Ahmed, Emory University; Christian Klein, Roche Innovation Center Zurich; Pablo Umaña, Roche Innovation Center Zurich
• Language: English
• Date: 2022-09-28
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-022-05192-0
• Title of Journal or Parent Work: NATURE
• Volume: 610
• Issue: 7930
• Start Page: 161
• End Page: +
• Keywords: Science & Technology; CHRONIC INFECTION; HOMEOSTASIS; EXPRESSION; Multidisciplinary Sciences; SUBSETS; INTERLEUKIN-2; LYMPHOCYTES; EXHAUSTION; Science & Technology - Other Topics; IMMUNE-RESPONSE; INDUCTION
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Expansion and differentiation of antigen-experienced PD-1+TCF-1+ stem-like CD8+ T cells into effector cells is critical for the success of immunotherapies based on PD-1 blockade1–4. Hashimoto et al. have shown that, in chronic infections, administration of the cytokine interleukin (IL)-2 triggers an alternative differentiation path of stem-like T cells towards a distinct population of ‘better effector’ CD8+ T cells similar to those generated in an acute infection5. IL-2 binding to the IL-2 receptor α-chain (CD25) was essential in triggering this alternative differentiation path and expanding better effectors with distinct transcriptional and epigenetic profiles. However, constitutive expression of CD25 on regulatory T cells and some endothelial cells also contributes to unwanted systemic effects from IL-2 therapy. Therefore, engineered IL-2 receptor β- and γ-chain (IL-2Rβγ)-biased agonists are currently being developed6–10. Here we show that IL-2Rβγ-biased agonists are unable to preferentially expand better effector T cells in cancer models and describe PD1-IL2v, a new immunocytokine that overcomes the need for CD25 binding by docking in cis to PD-1. Cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell recovers the ability to differentiate stem-like CD8+ T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models and provides superior efficacy. By contrast, PD-1- or PD-L1-blocking antibodies alone, or their combination with clinically relevant doses of non-PD-1-targeted IL2v, cannot expand this unique subset of better effector T cells and instead lead to the accumulation of terminally differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of PD-1 cis-targeted IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.