B7-H1 blockade plus regulatory T cell depletion improves clinical efficacy over either strategy alone in a melanoma model (P4268)

Abstract

Abstract Denileukin diftitox (DD) is an FDA-approved conjugate of human IL-2 + diphtheria toxin. It depletes Tregs and improves clinical and immune outcomes, but Treg generation can reduce efficacy. B7-H1 is an immune co-signaling molecule that promotes Treg generation and hinders anti-cancer immunity. αB7-H1 or DD each slowed tumor growth and improved anti-tumor immunity in B16 melanoma. DD reduced Treg numbers but αB7-H1 also reduced Treg suppression. In vitro, αB7-H1 reduced Treg generation from naïve CD4+CD25- T cells. We thus hypothesized that αB7-H1 would synergistically improve clinical efficacy of Treg depletion with DD by slowing regeneration or function of Tregs after depletion. We treated mice 7 days after B16 challenge when detectable tumors were present. DD+αB7-H1 significantly slower tumor growth at 25 days (avg tumor ~600 mm3 vs either single agent treatments (avg 1500-2000 mm3; p <0.05). Spleen CD4+ and CD8+ T cells with combined therapy showed significantly more activated CD44+CD62L- cells vs individual treatments, but we found no significant difference in T cell interferon-γ or IL-17 in treatment groups. Strikingly, we also did not detect reduced Treg function or numbers in DD + αB7-H1 combination vs individual treatments in spleen cells. Preliminary data suggest that effects are primarily in tumor draining lymph nodes, which are under current study. We use FDA approved agents like DD or agents in clinical trials such as αB7-H1 for rapid clinical translation.