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Retraction Free access | 10.1172/JCI129689

Targeting CD137 enhances the efficacy of cetuximab

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, and Ronald Levy

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Published June 3, 2019 - More info

Published in Volume 129, Issue 6 on June 3, 2019
J Clin Invest. 2019;129(6):2595–2595. https://doi.org/10.1172/JCI129689.
© 2019 American Society for Clinical Investigation
Published June 3, 2019 - Version history
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Related article:

Targeting CD137 enhances the efficacy of cetuximab
Holbrook E. Kohrt, … , John Sunwoo, Ronald Levy
Holbrook E. Kohrt, … , John Sunwoo, Ronald Levy
Research Article

Targeting CD137 enhances the efficacy of cetuximab

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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

×

Original citation: J Clin Invest. 2014;124(6):2668–2682. https://doi.org/10.1172/JCI73014

Citation for this retraction: J Clin Invest. 2019;129(6):2595. https://doi.org/10.1172/JCI129689

Stanford University School of Medicine recently notified the JCI of concerns regarding Figure 4, B, C, and E, Figure 5, B, D, and F, and Figure 6B and indicated that the original source data for these figures could not be located. In accordance with the institutional recommendation, the JCI is retracting this article.

Footnotes

See the related article at Targeting CD137 enhances the efficacy of cetuximab.

Version history
  • Version 1 (June 3, 2019): Print issue publication

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