Concurrent PD 1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T cell Apoptosis
Simultaneous treatment of mice with checkpoint inhibitor anti PD 1 and agonist anti OX40 negated the benefits of anti OX40 alone, due to increased apoptosis of CD8+ T cells. Thus, for clinical success, sequencing optimization for combination immunotherapy is crucial. Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD 1 or its ligand (PD L1) together with immune stimulatory agonist Abs like anti OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD 1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti PD 1 to anti OX40 negated the antitumor effects of OX40 Ab. Antigen specific CD8+ T cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNg producing E7 specifc CD8+ T cells in the spleens of mice treated with the combination of PD 1 blockade with anti OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti PD 1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. Cancer Immunol Res; 5(9) 755 66. (c)2017 AACR.
Cancer Immunology Research