Combination of IL-2/anti-IL-2 antibody complexes synergize with PD-1 and CTLA-4 pathway blockade by different cellular mechanisms
PC Caudana1, NG Nuñez1, A Pinto, P De La Rochere1, LL Niborski1, J Denizeau1, R Alonso1, O Lantz1, C Sedlik1, and E Piaggio1 1Paris-Sciences-Lettres, Institut Curie Research Center, INSERM U932 & SiRIC, Translational Immunotherapy Team
High dose IL-2 administration is one of the first treatments that demonstrate that manipulation of the immune system can induce durable cancer regression.. Yet, IL-2 therapy can be very toxic and the reached efficacy is not optimal, in part due to the unwanted effect of IL-2 on Tregs, which block the anti-tumor immune response. Unwanted activation of Tregs can be avoided by the use of IL-2/anti-IL-2 antibody (IL-2C) complexes, that re-direct IL-2 action to CD8+ T and NK cells. Moreover, IL-2Cs have a longer half-life, accounting for a better pharmacodynamics and can be used at lower doses, reducing toxicity. In this study, we evaluated whether combining IL-2C administration with the blockade of inhibitory immune pathways could result in an effective therapy. We used two experimental models: i) the B16-OVA, naturally resistant to anti-checkpoint inhibition and, ii) the K-rasLSL-G12D/+;p53fl/fl (KP) LUC.. genetically-engineered mouse lung adenocarcinoma that we modify to express MHCII and MHCI restricted antigen: DBY and OVA-I respectively. The modify KP mice express also the enzyme Luciferase, allowing us to follow the tumor development by luminescence. We observed that in both models, combination of IL-2C with blockade of the PD-1 or CTLA-4 pathways showed enhanced effectiveness, leading to complete tumor regression in some mice. We analysed tumor-specific T cell responses by multi-parametric flow-cytometry and ELISPOT. Mechanistic studies indicated that the combined treatments work by activating NK cells and/or re-invigorating exhausted CD8+ T cells infiltrating the tumor. To further investigate the cellular mechanisms, we wonder whether the different treatment could affect not only the quality of the infiltration, but also the manner by the cells infiltrate the tumor. To assess this, we used confocal microscopy in thick slide of tumor to track the different T cells and not T cell populations. Overall, our pre-clinical results indicate that combination of IL-2C with anti-checkpoint mAbs represent a valid therapeutic approach for fighting against cancer, worth being translated into the clinic.