SA-4-1BBL as an adjuvant component of tumor vaccines achieves better therapeutic efficacy than an agonistic 4-1BB antibody by limiting the frequency of regulatory T cells (156.8)

Abstract

Abstract Costimulation through 4-1BB receptor is important for the generation of CD8+ T cell responses critical for the control of tumors. As such, this pathway has been targeted for tumor immunotherapy using agonistic 4-1BB Abs. However, the use of Abs is associated with severe toxicity. We recently developed a nontoxic form of soluble 4-1BBL, SA-4-1BBL, and demonstrated that it delivers quantitatively and qualitatively improved signals to T cells than an agonistic 4-1BB Ab (3H3). We herein demonstrate that SA-4-1BBL as the adjuvant component of HPV E7 and survivin TAA-based vaccines shows better therapeutic efficacy than the 3H3 Ab in E7 expressing TC-1 cervical and survivin over expressing 3LL lung cancer mouse models. The better therapeutic efficacy of SA-4-1BBL was associated with its ability to restrict the frequency of CD4+CD25+Foxp3 Treg cells. In marked contrast, mice vaccinated with 3H3 Ab had dramatically increased numbers of Treg cells. Importantly, in vivo depletion of Treg cells using an Ab to CD25 significantly enhanced the efficacy of 3H3, but not SA-4-1BBL, based vaccine. Taken together, these data demonstrate that SA-4-1BBL serves as a better alternative to agonistic Abs to 4-1BB receptor for the development of cancer vaccines due to its safety and ability to diminish the incidence of regulatory T cells.