Immuno-oncology

Oral

T. 111 - Evaluation of TNFR2 Antagonism with and without Anti-PD-1 Therapy in Murine Colon Cancer Models

Co-Author(s)

• KC

  Katie Case, BS

  Massachusetts General Hospital/Harvard Medical School
• LT

  Lisa Tran, BS

  Massachusetts General Hospital/Harvard Medical School

Presenting Author(s)

• DF

  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.