A Multifunctional Role For Adjuvant Anti-4-1bb Therapy In Augmenting Antitumor Response By Chimeric Antigen Receptor T Cells

Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic alpha-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of a-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human Her2 self-antigen mouse model, we report here that alpha-41BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFN gamma and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with alpha-4-1BB. Strikingly, alpha-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that a-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with alpha-4-1BB against various types of cancer. (C)2017 AACR.