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Immuno-oncology
Oral
Katie Case, BS
Massachusetts General Hospital/Harvard Medical School
Lisa Tran, BS
Massachusetts General Hospital/Harvard Medical School
Denise Faustman, MD, PhD
Director of Immunobiology/Associate Professor of Medicine
Massachusetts General Hospital/Harvard Medical School
TNFR2 in humans and mice is central to immune balance control, acting on regulatory T cells (Tregs) and T effectors (Teffs) in opposing ways and serving as an oncogene in select cancers. Indeed, published work suggests TNFR2 is the bidirectional switch for Treg expansion/depletion, and TNFR2 derangements have been identified in diverse human and murine cancers.
We identified a murine-directed surrogate antibody to TNFR2 (TY101) that shares certain traits identified in human-directed antibodies as critical to limiting Treg expansion and activating Teff function.
In MC38 and CT26 murine colon tumor models, we compared: anti-TNFR2 therapy (TY101); a commercially available anti-PD1 therapy; and anti-TNFR2/anti-PD1 combination immunotherapy. Mice were dosed bi-weekly (100ug/mouse antibody) to test the impact on tumor growth. Antigen-specific CD8 and Treg infiltrates were studied within the tumor to evaluate possible tumor microenvironment changes secondary to therapy.
Single-agent anti-TNFR2 (MC38, p=0.04; CT26, p<0.001) and anti-PD1 (MC38, p=0.005; CT26, p=0.002) enhanced murine survival in both models. Combination immunotherapy was the most effective treatment in the MC38 model (p=0.004), but less beneficial than either single-agent in the CT26 model.
In situ tumor flow cytometry showed that single-agent anti-TNFR2 depleted intra-tumor Tregs (both models) and induced infiltrating CD8 Teff expansion (MC38 model), whereas anti-PD1 had no tumor microenvironment effects.
We conclude that anti-TNFR2 immunotherapy provides benefits in two murine colon tumor models, both with and without anti-PD1. Anti-TNFR2 was distinct from anti-PD1 therapy in showing pronounced Treg depletion and enhanced Teff infiltration in the tumor microenvironment.