Targeting CD137 enhances the efficacy of cetuximab
Holbrook E. Kohrt, … , John Sunwoo, Ronald Levy
Holbrook E. Kohrt, … , John Sunwoo, Ronald Levy
Published May 16, 2014
Citation Information: J Clin Invest. 2014;124(6):2668-2682. https://doi.org/10.1172/JCI73014.
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Research Article

Targeting CD137 enhances the efficacy of cetuximab

Abstract

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.

Authors

Holbrook E. Kohrt, A. Dimitrios Colevas, Roch Houot, Kipp Weiskopf, Matthew J. Goldstein, Peder Lund, Antonia Mueller, Idit Sagiv-Barfi, Aurelien Marabelle, Ruth Lira, Emily Troutner, Lori Richards, Amanda Rajapaska, Jonathan Hebb, Cariad Chester, Erin Waller, Anton Ostashko, Wen-Kai Weng, Lieping Chen, Debra Czerwinski, Yang-Xin Fu, John Sunwoo, Ronald Levy

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Figure 3

Cetuximab mAb induces CD137 expression in vivo.

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Cetuximab mAb induces CD137 expression in vivo. nu/nu mice were inoculat...
nu/nu mice were inoculated with 1 × 106 SCC6 tumor cells s.c. on the left flank, and cetuximab was administered on day 21 after tumor inoculation (A, schema). (B) Representative CD137 expression on CD3–DX5+ cells isolated from the spleen or peripheral blood 24 hours following cetuximab treatment or isotype control in non–tumor-bearing mice (n = 3 mice per group). (C) Representative CD3–DX5+ cells isolated from the spleen, peripheral blood, or tumor analyzed for CD137 expression 24, 72, or 168 hours following cetuximab treatment or isotype control in tumor-bearing mice (n = 3 mice per group). For B and C, numbers indicate percentage of cells above and below upper limit of isotype control.