Using two murine colon cancer models (CT26 and MC38), Case et al. evaluated the in vivo efficacy of anti-TNFR2 antibody as monotherapy and in combination with anti-PD-1. Anti-TNFR2 in combination with anti-PD-1 demonstrated the best tumor reduction, with 62% and 70% cure rate in CT26 and MC38, respectively. The enhanced efficacy of anti-TNFR2 in combination with anti-PD-1 was accompanied by decrease in Tregs and increase in CD8+ T cell/Treg ratio. Co-administration of anti-TNFR2 with anti-PD-1 was the best schedule, with 70% cure rate compared to anti-TNRF2 followed by anti-PD1 (40%), and anti-PD-1 followed by anti-TNRF2 (10%).
Contributed by Shishir Pant
ABSTRACT: Immune checkpoint inhibitors are profoundly transforming cancer therapy, but response rates vary widely. The efficacy of checkpoint inhibitors, such as anti-programmed death receptor-1 (anti-PD-1), might be increased by combination therapies. TNFR2 has emerged as a new target due to its massive expression on highly immunosuppressive regulatory T cells (Tregs) in the microenvironment and on certain tumor cells. In murine colon cancer models CT26 and MC38, we evaluated the efficacy of a new anti-TNFR2 antibody alone or in combination with anti-PD-1 therapy. Tumor-bearing mice were treated with placebo, anti-PD-1 alone, anti-TNFR2 alone, or combination anti-PD-1 and anti-TNFR2. We found that combination therapy had the greatest efficacy by complete tumor regression and elimination (cure) in 65-70% of animals. The next most effective therapy was anti-TNFR2 alone (20-50% cured), whereas the least effective was anti-PD-1 alone (10-25% cured). The mode of action, according to in vivo and in vitro methods including FACS analysis, was by killing immunosuppressive Tregs in the tumor microenvironment and increasing the ratio of CD8+ T effectors (Teffs) to Tregs. We also found that sequence of antibody delivery altered outcome. The two most effective sequences were simultaneous delivery (70% cured) followed by anti-TNFR2 preceding anti-PD-1 (40% cured), and the least effective was by anti-PD-1 preceding anti-TNFR2 (10% cured). We conclude that anti-PD-1 is best enhanced by simultaneous administration with anti-TNFR2, and anti-TNFR2 alone may be potentially useful strategy for those do not respond to, or cannot tolerate, anti-PD-1 or other checkpoint inhibitors.
Author Info: (1) Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. (2) Immunobiology Laboratory, Massachusetts General Hospital an
Author Info: (1) Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. (2) Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. (3) Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. (4) Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA. (5) Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA. (6) Immunobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
