Abstract 2256: Combination of neoantigen DNA plasmid vaccine VB10.NEO and NKTR-214, a CD122-biased immunostimulatory cytokine, induces strong neoantigen-specific T cell responses and sustained tumor regression in pre-clinical models
Authors: Granum Stine , Zell-Flagstad Helene , Bersaas Audun , Skullerud Lise , Müller Elisabeth , Axelsen Mads , Schjetne Karoline , Zalevsky Jonathan , Fredriksen Agnete 
Published: August 2019

BACKGROUND: VB10.NEO is a highly potent DNA plasmid vaccine with intrinsic adjuvant effect designed for efficient delivery of personalized neoepitopes and is currently being tested in combination with CPI in patients with advanced solid tumors. NKTR-214, a CD122-biased agonist that targets the IL-2 pathway, provides sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβγ) to preferentially activate and expand NK and effector CD8+ T cells over T-regulatory cells, and is currently in multiple phase I, II and III clinical trials in combination with nivolumab. Here we explored the combination of VB10.NEO with NKTR-214 in the presence or absence of anti-PD-1 therapy in different pre-clinical syngeneic tumor models.

METHODS: Mice were vaccinated with VB10.NEO (i.m.), NKTR-214 (i.v) and anti-PD-1 (i.p.) at different intervals to study efficacy and optimal dosing schedule before spleens were harvested to analyze CD8+ and CD4+ neoantigen-specific T cell responses in IFN-γ ELISpot in two different tumor models (B16 and CT26). The tumor protective effect of the combination therapy of VB10.NEO with NKTR-214 in the presence or absence of anti-PD-1 therapy was investigated in CT26 colon carcinoma model.

RESULTS: Combination of VB10.NEO and NKTR-214 greatly synergizes, resulting in 5-fold increase in the number of neoantigen-specific T cell responses compared to VB10.NEO alone. Dosing of VB10.NEO vaccination relative to NKTR-214 administration was found to impact the extent of the synergetic activity. Mice treated with VB10.NEO containing 10 neoepitopes from B16 in combination with NKTR-214 showed both a stronger response to each neoantigen, but also to increased numbers of neoantigens, showing that both the breadth and depth of the immune response were elevated. The VB10.NEO and NKTR-214 combination showed an even more evident effect on CD8+ T cell responses as the combination elicited a neoantigen-specific CD8+ T cell response against 10 neoantigens compared to 5 neoantigens with VB10.NEO alone, further strengthening the combination’s ability to induce strong neoantigen-specific CD8+ T cell responses. In the therapeutic tumor model, increased number of complete responders was observed in mice treated with the triple combination of vaccine, NKTR-214 and CPI demonstrating the strong rational for bringing together these unique and non-overlapping mechanisms that create an effective treatment of established tumors.

CONCLUSION: VB10.NEO in combination with NKTR-214 with or without anti-PD-1 therapy synergizes to elicit greater breadth and depth of neoantigen-specific T cell responses and provide durable complete tumor regression in pre-clinical models supporting the rationale for examining the combination clinically.

Citation Format: Stine Granum, Helene Zell-Flagstad, Audun Bersaas, Lise Skullerud, Elisabeth Müller, Mads Axelsen, Karoline Schjetne, Jonathan Zalevsky, Agnete Fredriksen. Combination of neoantigen DNA plasmid vaccine VB10.NEO and NKTR-214, a CD122-biased immunostimulatory cytokine, induces strong neoantigen-specific T cell responses and sustained tumor regression in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2256.