Abstract 2217: Combining CEA-IL2v and FAP-IL2v immunocytokines with PD-L1 checkpoint blockade
Authors: Nicolini Valeria , Waldhauer Inja , Freimoser-Grundschober Anne , Evers Stefan , Saro Jose , Bacac Marina , Gerdes Christian , Umana Pablo , Klein Christian 
Published: July 2016

Abstract
Introduction: CEA-IL2v (RG7813, RO6895882) and FAP-IL2v (RG7461, RO6874281) are novel CEA-/FAP-targeted immunocytokines based on a novel IL2 variant (IL2v) with abolished CD25 binding that are currently in clinical phase 1 trials. PD-L1 is found on the surface of cells in various tumors and is induced by interferon gamma (IFNg). It prevents the immune system from destroying cancer cells by interacting with the inhibitory receptors PD-1 and B7.1 on T cells. Atezolizumab blocks the interaction of PD- L1 with its receptors and is currently being investigated in pivotal clinical trials for various cancers.
Materials and Methods: PD-L1 expression on A549 tumor cells was analyzed by flow cytometry after treatment with CEA-IL2v alone or in the presence of PBMCs at varying E:T ratios. The combination of muCEA-IL2v, a murinized version of CEA-IL2v, with a muPD-L1 specific surrogate antibody was investigated in syngeneic stably CEA expressing PancO2 and MC38 cell lines in human CEA transgenic C57BL/6 mice. As control an untargeted DP47-muIL2v control immunocytokine was applied in the PancO2-CEA model. The combination of muFAP-IL2v, a murinized version of FAP-IL2v, with a muPD-L1 specific surrogate antibody was investigated in a syngeneic stably FAP expressing MC38 cell line in C57BL/6 mice.
Results: In vitro, co-cultures of human PBMCs and the human A549 lung cancer cell line showed that CEA-IL2v induces the up-regulation of PD-L1 on A549 tumor cells in a concentration-dependent manner mediated through release of IFNg. In the syngeneic s.c. MC38-CEA model in CEA/hCD16 transgenic C57BL/6 mice, muCEA-muIL2v (0.5 mg/kg, q1wx2) and the muPD-L1 antibody (10 mg/kg, q1wx2) resulted in superior combined efficacy compared to the respective single agent therapies with respect to tumor growth inhibition. In the syngeneic orthotopic Panc02-CEA model in CEA transgenic C57BL/6 mice, muCEA-muIL2v (0.25 mg/kg, q1wx4) and the muPD-L1 antibody (10 mg/kg, q1wx4) resulted in superior median and overall survival model compared to the respective single agent therapies. Notably, the combination of muCEA-muIL2v was superior to the combination of the untargeted DP47-muIL2v control immunocytokine (exposure matched dose: 0.2 mg/kg, q1wx4) with the muPD-L1 antibody. Similarly, in the syngeneic s.c. MC38-FAP model the combination of muFAP-muIL2v (2 mg/kg, q1w4) and the muPD-L1 antibody (10 mg/kg, q1w4) resulted in superior combined efficacy compared to the respective single agent therapies in terms of tumor growth inhibition as well as median and overall survival.
Conclusions: Taken together these nonclinical combination data support the clinical testing of combinations of CEA-IL2v and FAP-IL2v with atezolizumab. A clinical Phase 1b study combining CEA-IL2v and atezolizumab is currently ongoing (NCT02350673).
Citation Format: Valeria Nicolini, Inja Waldhauer, Anne Freimoser-Grundschober, Stefan Evers, Jose Saro, Marina Bacac, Christian Gerdes, Pablo Umana, Christian Klein. Combining CEA-IL2v and FAP-IL2v immunocytokines with PD-L1 checkpoint blockade. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2217.