Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma

Abstract

Combinations of mAbs 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 coinhibitory T-cell receptors. .

Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

“…In a model of B cell lymphoma, McKee et al recently demonstrated an abrogation of the therapeutic effect of 4-1BB costimulation when anti-PD-1 was combined concurrently (43). In our studies, concurrent anti-OX40 and anti-PD-1 also attenuated anti-OX40-induced therapeutic efficacy, dramatically increased serum cytokine levels, and increased peripheral T cell apoptosis.…”

Chemotherapy followed by anti-CD137 mAb immunotherapy improves disease control in a mouse myeloma model

“…These results are disappointing given the promising potential of combining CD137 stimulation with PD-1/PD-L1 blockade in solid tumors (33). Nevertheless, it was recently reported that PD-1 blockade abrogates the therapeutic efficacy of anti-CD137 mAbs in the Eμ-MYC model of mouse lymphoma (34). In agreement with this report, our data emphasize the need for a better understanding of the underlying immune responses to combi-nation therapies to define the specific cancer types and conditions where they might be beneficial.…”

Switching on the green light for chimeric antigen receptor T‐cell therapy

“…23,24 Interestingly, however, a study by Messenheimer et al found that when a-OX40 and a-PD-1 antibodies were administered sequentially by treating MMTV-PyMT tumor-bearing mice with a-OX40 mAb before a-PD-1 mAb, the sequential combination therapy resulted in augmented antitumor efficacy. 25 The reason for the discrepancies observed between different studies involving checkpoint inhibitor and immune agonist combination is not completely understood; however, the dose and timing of the immune-modulating antibody administration may be of high importance. 23 Further, another study that tested the combination of a-4-1BB and a-PD-1 antibodies in a murine spontaneous B-cell lymphoma model found that simultaneous use of a-PD-1 mAb diminished the antitumor activity of a-4-1BB mAb alone.…”

“…The mechanism for this effect was thought to be due to a dramatic reduction in the function of effector CD8 + T cells in the presence of a-PD-1 mAb, potentially through induced apoptosis. 25 The reason for the discrepancies observed between different studies involving checkpoint inhibitor and immune agonist combination is not completely understood; however, the dose and timing of the immune-modulating antibody administration may be of high importance.…”