CD137 Activation Augments the Efficacy of EGFR-Targeted Therapy

The EGFR-targeting mAb cetuximab is approved for the treatment of head and neck and colorectal cancers; however, many patients show limited response or no response to cetuximab, including those with KRAS-mutant tumors. The antitumor activity of cetuximab requires antibody-dependent cell-mediated cytotoxicity (ADCC) driven by natural killer (NK) cells, suggesting that strategies that enhance ADCC may improve the efficacy of cetuximab. Kohrt and colleagues found that expression of CD137 (also known as TNFRSF9 or 4-1BB) on NK cells was upregulated in response to cetuximab-treated EGFR-positive tumor cells both in vitro and in tumor-bearing mice. Dual treatment with cetuximab and an agonistic anti-CD137 mAb augmented NK cell–mediated ADCC of tumor cells and synergistically suppressed tumor growth in mice more efficiently than did cetuximab treatment alone, resulting in prolonged survival. Intriguingly, sequential treatment with cetuximab followed by anti-CD137 mAb induced regression of both KRAS–wild-type and KRAS-mutant tumors, suggesting that this therapeutic approach may overcome cetuximab resistance. This improved antitumor activity was dependent on NK cells as well as a CD8⁺ T-cell adaptive immune response, with increased IFNγ production and epitope spreading beyond EGFR. Of note, cetuximab therapy in patients with head and neck cancer was correlated with increased CD137 expression on circulating and intratumoral NK cells, particularly among patients harboring high-affinity Fcγ receptor III alleles, and an increased proportion of EGFR-specific CD8⁺ T cells. These results define a therapeutic strategy that enhances the efficacy of cetuximab by sequentially targeting tumor cells and tumor-associated NK cells and stimulating cross-talk between innate and adaptive immune cells. In addition, these findings suggest that this approach may be more broadly useful for the treatment of EGFR-expressing tumors.

Kohrt HE, Colevas AD, Houot R, Weiskopf K, Goldstein MJ, Lund P, et al. Targeting CD137 enhances the efficacy of cetuximab. J Clin Invest 2014;124:2668–82.

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