Differentiating PD-1+ stem-like CD8 T cells towards distinct effectors with enhanced therapeutic potential by an engineered IL-2 cis-targeted to PD-1
Authors: Umaña Pablo , Deak Laura Codarri , Hashimoto Masao , Ahmed Rafi , Klein Christian , Nicolini Valeria , Lauener Laura , Karagianni Maria , Richard Marine , Bommer Esther , Sam Johannes , Perro Mario , Cremasco Floriana , Kunz Leo , Schlenker Ramona , Mariani Marisa , Tosevski Vinko , Schwalie Petra , Herter Sylvia , Bacac Marina , Waldhauer Inja , Colombetti Sara , Leclair Stephane , Freimoser-Grundschober Anne , Seeber Stefan , Teichgräber Volker 
Published: March 2021

Abstract
Expansion of antigen-specific effector CD8 T cells is central to the control of chronic viral infections and cancer. In particular, differentiation of antigen-experienced, PD-1+TCF-1+ stem -like CD8 T cells, termed here “resource T cells”, into effector cells is critical for the success of immunotherapies based on immune checkpoint PD-1 signaling blockade1-4. In the accompanying article, Hashimoto et al. show that in chronic infections, administration of the cytokine interleukin- 2 (IL-2) triggers an alternative differentiation path from resource T cells leading to the expansion of a distinct population of effector CD8 T cells, termed “better effectors”, which are similar to effector cells generated in an acute infection. IL-2 binding to the non-signaling component of its receptor, IL-2Rα-chain, also known as CD25, was essential to trigger this alternative differentiation path and to expand better effectors with distinct transcriptional and epigenetic profiles. However, as IL-2 binding to CD25 constitutively expressed on immunosuppressive regulatory T cells and on some endothelial cells contributes to unwanted systemic effects of IL-2 therapy that have hampered its broad clinical application, a new generation of engineered IL-2Rβγ-biased agonists with reduced/abolished CD25 binding is currently being developed5-9. Here we show that IL-2Rβγ-biased agonists devoid of CD25 binding are unable to preferentially expand better effectors in cancer models, and describe a novel antibody-cytokine fusion protein, PD1-IL2v, that overcomes the need for CD25 binding by using PD-1 binding in cis in order to generate this distinct effector cell population. PD1-IL2v comprises an engineered IL-2 variant devoid of CD25 binding, fused to a high affinity PD-1 blocking antibody. In cis binding of PD1-IL2v to PD-1 and IL-2Rβγ on the same cell surface recovers the ability to differentiate resource CD8 T cells into better effectors in the absence of CD25 binding in both chronic infection and cancer models, while providing superior treatment efficacy. In contrast, PD-1/-L1 blocking antibodies alone, or their combination with clinically relevant doses of IL-2-based molecules with abolished CD25 binding and not targeted to PD-1, could not expand this unique subset of better effector T cells, and rather led to the accumulation of terminally-differentiated, exhausted T cells. These findings provide the basis for the development of a new generation of IL-2R agonists with enhanced therapeutic potential for the treatment of cancer and chronic infections.