TY - JOUR AU - Kohrt, Holbrook E. AU - Colevas, A. Dimitrios AU - Houot, Roch AU - Weiskopf, Kipp AU - Goldstein, Matthew J. AU - Lund, Peder AU - Mueller, Antonia AU - Sagiv-Barfi, Idit AU - Marabelle, Aurelien AU - Lira, Ruth AU - Troutner, Emily AU - Richards, Lori AU - Rajapaska, Amanda AU - Hebb, Jonathan AU - Chester, Cariad AU - Waller, Erin AU - Ostashko, Anton AU - Weng, Wen-Kai AU - Chen, Lieping AU - Czerwinski, Debra AU - Fu, Yang-Xin AU - Sunwoo, John AU - Levy, Ronald T1 - Targeting CD137 enhances the efficacy of cetuximab PY - 2014/06/02/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI73014 VL - 124 IS - 6 UR - https://doi.org/10.1172/JCI73014 SP - 2668 EP - 2682 PB - The American Society for Clinical Investigation ER -