Abstract B77: TNFR2 blockade alone or in combination with PD-1 blockade shows therapeutic efficacy in murine cancer models
Authors: LaMontagne Russell , Case Katie , Tran Lisa , Zheng Hui , Yang Michael , Faustman Denise 
Published: March 2020

Abstract
Tumor necrosis factor receptor 2 (TNFR2) is central to immune balance control in humans and mice. We created human-directed anti-TNFR2 antibodies as a therapeutic approach in cancer, with positive findings (Torrey H, et al. Sci Signal 2017). We have also identified a murine-directed surrogate antagonistic antibody to TNFR2. This antibody shares traits identified in our human-directed antibodies as critical to limiting regulatory T cell (Treg) expansion and activating T effector (Teff) cells. We now present data on this surrogate anti-TNFR2 antibody in two syngeneic mouse models of colon cancer. To study the therapeutic effects of solo and combined immunotherapy using the murine-directed anti-TNFR2 antibody, we used CT26 and MC38 colon tumor models to compare: (i) the murine-directed surrogate anti-TNFR2 antibody therapy, (ii) a commercially available anti-PD1 therapy, and (iii) anti-TNFR2/anti-PD1 combination immunotherapy. Mice were dosed bi-weekly (100ug/mouse antibody). Antigen-specific CD8 and Treg infiltrates were also studied. Mice were tested and monitored for tumor growth by either Champions Oncology (Hackensack, NJ) or a third-party pharmaceutical company in accordance with their respective animal welfare guidelines. In the CT26 model, anti-TNFR2 antagonism alone or cotreatment with anti-PD1 and anti-TNFR2 was highly efficacious (55-62% of mice cured). Anti-PD1 alone was less efficacious (25% cured). In the MC38 model, therapy with anti-TNFR2 alone showed some efficacy (20% cured), anti-PD1 alone had the least efficacy (10% cured), and anti-PD1 in combination with anti-TNFR2 yielded the best overall survival (70% cured). Sequential antibody dosing with anti-PD1 followed by anti-TNFR2 showed no synergy. In contrast, sequential treatment with anti-TNFR2 first followed by anti-PD1, or the combination of anti-TNFR2 plus anti-PD1, showed synergy and highest efficacy. Anti-TNFR2 therapy was distinct from anti-PD1 in showing pronounced Treg depletion and enhanced Teff infiltration in the tumor microenvironment, demonstrating in vivo specificity for disease-causing cells only in the tumor. Anti-TNFR2 immunotherapy provides benefits in two colon cancer models, both as a single agent and when administered in combination with anti-PD1. Anti-PD1 before anti-TNFR2 was associated with poor outcomes for survival, histology, and lack of long-term cure, suggesting that nonspecific unleashing of the immune system with anti-PD1 destroys the tumor microenvironment specificity of anti-TNFR2. These results highlight the value of anti-TNFR2 antagonism in vivo in mouse tumor models as solo therapy or as a combination therapy, administered first or concurrently with anti-PD1. This study of new immunotherapy combinations highlights the need to test both single-agent therapy and sequential combination therapy as new agents are brought forward to the clinic.
Citation Format: Russell LaMontagne, Katie Case, Lisa Tran, Hui Zheng, Michael Yang, Denise Faustman. TNFR2 blockade alone or in combination with PD-1 blockade shows therapeutic efficacy in murine cancer models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B77.