Combinations of monoclonal antibodies (mAb) that target various components of T-cell activation/inhibition may work synergistically to improve antitumor immunity against cancer. In this study we investigated the therapeutic potential of combining an anticancer vaccination strategy with antibodies targeting an immune stimulatory (4-1BB) and immune inhibitory (PD-1) receptor, in a preclinical model of spontaneously arising c-Myc-driven B-cell lymphoma. In Eμ-myc transgenic mice we reveal that 4-1BB agonistic mAb treatment alone was sufficient to drive antitumor immunity and prevent disease progression in 70% of mice. When combined with an α-GalCer-loaded, irradiated tumor cell vaccine, 4-1BB mAb treatment led to increased expansion of effector CD8 T-cell populations and protection of long-term surviving mice against tumor rechallenge. Unexpectedly, PD-1 blockade did not provide therapeutic benefit. The T-cell promoting effects and antitumor activity of 4-1BB mAb were diminished when used simultaneously with a PD-1 blocking mAb. This was associated with a rapid and dramatic reduction in effector CD8+ T-cell subsets in the presence of PD-1 blockade. These findings reveal that supporting T-cell activation therapeutically is effective for controlling B-cell lymphomas, however caution is required when combining antibody-mediated modulation of both costimulatory and co-inhibitory T-cell receptors.
- Received September 26, 2016.
- Revision received December 12, 2016.
- Accepted January 6, 2017.
- Copyright ©2017, American Association for Cancer Research.