Anti-CD137 enhances anti-CD20 therapy of systemic B-cell lymphoma with altered immune homeostasis but negligible toxicity

ABSTRACT

Studies of sequential anti-CD137/anti-CD20 therapy have previously shown that the efficacy of anti-CD20 was heavily reliant upon anti-CD137; however, the exact mechanism of the anti-B-cell lymphoma efficacy, and whether this correlates with enhanced adverse effects or toxicity, had not been elucidated. Here, we observed that sequential anti-CD137 administration with anti-CD20 resulted in a synergistic therapy, largely dependent upon Fc receptors (FcR), to prolong survival in an experimental B-cell lymphoma therapy model. Tumor suppression was accompanied by B cell depletion, which was not dependent on one activating FcR. Surprisingly, the B-cell activating factor (BAFF) was elevated in the plasma of mice receiving anti-CD137 alone or in combination with anti-CD20, while a selective increase in some plasma cytokines was also noted and triggered by anti-CD137. These effects were independent of activating FcR. Sustained treatment of advanced lymphoma revealed increased lymphocyte infiltrates into the liver and a significant decrease in the metabolic capability of the liver in mice receiving anti-CD137. Importantly, these effects were not exacerbated in mice receiving the anti-CD20/CD137 combination, and elevations in classical liver damage markers such as alanine aminotransferase (ALT) were less than that caused by the lymphoma itself. Thus, combined anti-CD20/anti-CD137 treatment increases the therapeutic index of anti-CD20 or anti-CD137 alone. These mouse data were corroborated by ongoing clinical development studies to assess safety, tolerability and pharmacodynamic activity of human patients treated by this approach. Together, these data support the use of this sequential antibody therapeutic strategy to improve the efficacy of rituximab in B-cell lymphoma patients.

KEYWORDS:

• Adverse effects
• anti-CD137
• anti-CD20
• B-cell lymphoma
• combinations
• immunotherapy
• immune homeostasis

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

We thank Clay Winterford, Deborah Knight, Leesa Wockner, Liam Town, Nigel Waterhouse, Steven Lane, Tam Nguyen for providing technical support, reagents, discussion, comments, and advice in this project. The authors acknowledge Genentech for providing 5D2 mAb and Tom Tedder for the BL3750 lymphoma cells. This manuscript is dedicated to the memory of our colleague and friend, Dr. Holbrook Edwin Kohrt, who was a distinguished clinician scientist in the field of cancer immunotherapy.

Funding

M.J.S was supported by a National Health and Medical Research Council (NH&MRC) Senior Research Fellowship (1078671). F.S.F.G. was supported by a NH&MRC Early Career Fellowship (1088703), a National Breast Cancer Foundation (NBCF) Fellowship (PF-15-008), and Cancer Cure Australia Priority-Driven Young Investigator Project Grant (1082709).

Author contributions

F.S.F.G., H.E.K., and M.J.S. designed research, supervised work, and wrote the paper. F.S.F.G., S.B., A.M., C.C., and M.J.S. performed the research. F.S.F.G., H.E.K., and M.J.S. analyzed the data.