The Immunocytokine Pd1-Il2v Overcomes Immune Checkpoint Resistance, And Combination With An Anti-Pd-L1 Antibody Further Enhances Its Anti-Tumor Activity.

Abstract Cancer immunotherapies have shown therapeutic benefits in the clinic, but treatments involving immuno-stimulatory agents such as interleukin 2 (IL-2) are typically accompanied by severe adverse events. One strategy to limit the systemic toxicity of IL-2 is to target it specifically to the tumor microenvironment. Here we evaluated the therapeutic efficacy of the bi-specific immunocytokine PD1-IL2v in the genetically engineered, spontaneous RIP1-Tag5 (RT5) mouse model of pancreatic neuroendocrine tumors (PanNETs). PD1-IL2v is a bi-specific molecule based on a bivalent PD-1 antibody to which a single IL2 variant (IL2v) is fused. PD-1 serves as a targeting moiety to deliver IL2v in cis to PD-1-positive T cells located in the immune tumor microenvironment, and IL2v has been engineered to lack binding to CD25 in order to selectively expand effector T cells but not immuno-suppressive regulatory T cells (Tregs). Although RT5 mice are capable of mounting an adaptive immune response against the tumor-driving oncoprotein, PanNETs developing in RT5 are resistant to immune checkpoint inhibitors. In comparing the untargeted version of IL2v combined with an anti-PD-1 antibody vs. the PD-1 targeted immunocytokine PD1-IL2v, we found that PD1-IL2v, but not the mixture, produced significant anti-tumor activity. PD1-IL2v treatment resulted in a substantial infiltration of CD8+ T cells into the pancreatic islet tumors, which in the context of sustained treatment with PD1-IL2v resulted in tumor regression. Interestingly, following tumor shrinkage, the PanNETs appeared to stabilize and eventually relapsed. Notably, we identified up-regulation of PD-L1 on the tumor vasculature in relapsing tumors as a potential factor in the observed adaptive resistance, which encouraged combining an anti-PD-L1 antibody with PD1-IL2v, leading to enhanced therapeutic benefit. The data obtained in this spontaneous de novo tumor model motivate consideration of evaluating the PD1-IL2v/anti-PD-L1 combination therapy in the clinical setting, in particular in anti-PD-1/anti-PD-L1 resistant tumors infiltrated with PD1+CD8+ T cells. Citation Format: Stephan Wullschleger, Mélanie Tichet, Laura Codarri-Deak, Pablo Umana, Christian Klein, Douglas Hanahan. The immunocytokine PD1-IL2v overcomes immune checkpoint resistance, and combination with an anti-PD-L1 antibody further enhances its anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 71.