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 6

Anti-CD137 mAb enhances adaptive immunity following cetuximab.

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Anti-CD137 mAb enhances adaptive immunity following cetuximab. BALB/c mi...
BALB/c mice were inoculated with 1 × 106 TUBO-EGFR (red symbols) s.c. on the left flank and 1 × 106 TUBO tumor cells (black symbols) s.c. on the right flank (A, schema). After tumor inoculation, mice (15 per group) then received either rat IgG control on day 14 (circles), cetuximab on day 14 (triangles), or cetuximab on day 14 and anti-CD137 antibody on day 15 (diamonds), with each repeated 4 times weekly; animals were monitored for tumor growth (B, *P < 0.001; **P = 0.021). On day 24, TUBO and TUBO-EGFR tumors were resected from 5 untreated (NT, IgG control) mice and mice treated with cetuximab monotherapy and combination cetuximab and anti-CD137 mAb; animals were analyzed for percentage of total viable cells representing tumor-infiltrating DCs, NK cells, and CD4+ and CD8+ T cells (C, *P < 0.05, **P < 0.01, **P < 0.001). On day 24, PBMCs were collected from 5 untreated (black symbols) mice and mice treated with cetuximab monotherapy (white symbols) and combination cetuximab and anti-CD137 mAb (half-black symbols) and analyzed ex vivo for IFN-γ production following exposure to medium (negative control, circles), A20 (negative control, squares), TUBO (triangles), or TUBO-EGFR (diamonds) cell lines (D, *P = 0.009, **P < 0.001). Splenocytes were obtained from naive mice (total splenocytes, circles) or mice sacrificed 50 days following tumor inoculation and treatment with either cetuximab monotherapy (total splenocytes, CD8-selected, upside-down triangles) or sequential cetuximab and anti-CD137 mAb (total splenocytes, CD8-selected, triangles) and were coinjected (100:1) into naive mice (10 per group) with TUBO (E, *P < 0.001) or TUBO-EGFR (F, *P < 0.001) and monitored for percentage of mice that were tumor free.