Abstract 2774: The triple combination of the FAP-IL2v immunocytokine with PD-L1 checkpoint inhibitory and CD40 agonistic antibodies results in long-term tumor control in the orthotopic PancO2 model
Authors: Nicolini Valeria , Waldhauer Inja , Freimoser Anne , Corse Emily , Charo Jahad , Umana Pablo , Klein Christian 
Published: August 2018

Abstract
Introduction: We have previously described the FAP-targeted immunocytokine FAP-IL2v and its combination with PD-L1 checkpoint inhibition. Here we show that the anti-tumoral efficacy of FAP-IL2v can be strongly enhanced by combination with a CD40 agonistic antibody as well as the triple combination of FAP-IL2v with a CD40 agonistic and a PD-L1 checkpoint inhibitory antibody in the syngeneic PancO2 model. Methods: Anti-tumoral efficacy was assessed in the orthotopic intra-pancreatic PancO2 model transfected with Luciferase in C57BL/6 mice. Mice were injected intra-pancreatically on study day 0 with 1x10E5 Panc02-Fluc cells, randomized and weighed. One week after tumor cell injection mice were injected i.p. with the murine specific surrogate immunocytokine muFAP-muIL2v (muIgG1 DAPG) (2 mg/kg, q1wx3), anti-muPD-L1 surrogate antibody (muIgG1 DAPG) (10 mg/kg, q1wx3) and/or the anti-muCD40 surrogate antibody FGK4.5 (muIgG1) (10mg/kg, q1wx1). Bioluminescence imaging (BLI) was performed after ip injection of 150 mg/kg D-Luciferin 10 min before acquisition using IVIS® SPECTRUM. An analogous experiment was performed in C57BL/6 B cell knockout mice. Results: In the orthotopic PancO2-Fluc model the triple combination of FAP-IL2v plus anti-PD-L1 plus anti-CD40 showed superior outcome compared to vehicle and the respective monotherapies in terms of median survival and overall survival in the majority of animals followed by the combination of FAP-IL2v with anti-CD40 and the combinations of anti-PD-L1 with anti-CD40 and FAP-IL2v with anti-PD-L1, respectively. Bioluminescence imaging confirmed the survival outcome of the respective groups by decrease in/absence of bioluminescence signals in the tumor area. Tumor re-challenge experiments showed that the animals with long-term survival were protected both in the C57BL/6 and the C57BL/6 B cell knockout mice. Conclusions: These data show that the anti-tumoral efficacy of FAP-IL2v in the syngeneic PancO2 model can be strongly enhanced by combining it with a CD40 agonistic antibody on top of a PD-L1 checkpoint inhibitory antibody. Most notably, the triple combination of FAP-IL2v with CD40 agonism and PD-L1 checkpoint inhibition resulted in long term survival of the majority of animals. These data provide the preclinical rationale for further clinical investigation of the combination of FAP-IL2v (RG7461) with the PD-L1 antibody atezolizumab and the CD40 agonistic antibody selicrelumab (RG7876).
Citation Format: Valeria Nicolini, Inja Waldhauer, Anne Freimoser, Emily Corse, Jahad Charo, Pablo Umana, Christian Klein. The triple combination of the FAP-IL2v immunocytokine with PD-L1 checkpoint inhibitory and CD40 agonistic antibodies results in long-term tumor control in the orthotopic PancO2 model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2774.