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 CzerwinskiYang Xin Fu, John Sunwoo, Ronald Levy

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2668-2682
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number6
DOIs
StatePublished - Jun 2 2014
Externally publishedYes

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Natural Killer Cells
Head and Neck Neoplasms
Colorectal Neoplasms
Neoplasms
Antibody-Dependent Cell Cytotoxicity
T-Lymphocytes
Cell Degranulation
Heterografts
Cetuximab
Immune System
Immunoglobulin G
Cell Line
Survival
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kohrt, H. E., Colevas, A. D., Houot, R., Weiskopf, K., Goldstein, M. J., Lund, P., ... Levy, R. (2014). Targeting CD137 enhances the efficacy of cetuximab. Journal of Clinical Investigation, 124(6), 2668-2682. https://doi.org/10.1172/JCI73014

Targeting CD137 enhances the efficacy of cetuximab. / Kohrt, Holbrook E.; Colevas, A. Dimitrios; Houot, Roch; Weiskopf, Kipp; Goldstein, Matthew J.; Lund, Peder; Mueller, Antonia; Sagiv-Barfi, Idit; Marabelle, Aurelien; Lira, Ruth; Troutner, Emily; Richards, Lori; Rajapaska, Amanda; Hebb, Jonathan; Chester, Cariad; Waller, Erin; Ostashko, Anton; Weng, Wen Kai; Chen, Lieping; Czerwinski, Debra; Fu, Yang Xin; Sunwoo, John; Levy, Ronald.

In: Journal of Clinical Investigation, Vol. 124, No. 6, 02.06.2014, p. 2668-2682.

Research output: Contribution to journalArticle

Kohrt, HE, Colevas, AD, Houot, R, Weiskopf, K, Goldstein, MJ, Lund, P, Mueller, A, Sagiv-Barfi, I, Marabelle, A, Lira, R, Troutner, E, Richards, L, Rajapaska, A, Hebb, J, Chester, C, Waller, E, Ostashko, A, Weng, WK, Chen, L, Czerwinski, D, Fu, YX, Sunwoo, J & Levy, R 2014, 'Targeting CD137 enhances the efficacy of cetuximab', Journal of Clinical Investigation, vol. 124, no. 6, pp. 2668-2682. https://doi.org/10.1172/JCI73014
Kohrt HE, Colevas AD, Houot R, Weiskopf K, Goldstein MJ, Lund P et al. Targeting CD137 enhances the efficacy of cetuximab. Journal of Clinical Investigation. 2014 Jun 2;124(6):2668-2682. https://doi.org/10.1172/JCI73014
Kohrt, Holbrook E. ; Colevas, A. Dimitrios ; Houot, Roch ; Weiskopf, Kipp ; Goldstein, Matthew J. ; Lund, Peder ; Mueller, Antonia ; Sagiv-Barfi, Idit ; Marabelle, Aurelien ; Lira, Ruth ; Troutner, Emily ; Richards, Lori ; Rajapaska, Amanda ; Hebb, Jonathan ; Chester, Cariad ; Waller, Erin ; Ostashko, Anton ; Weng, Wen Kai ; Chen, Lieping ; Czerwinski, Debra ; Fu, Yang Xin ; Sunwoo, John ; Levy, Ronald. / Targeting CD137 enhances the efficacy of cetuximab. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 6. pp. 2668-2682.
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AU - Lund, Peder

AU - Mueller, Antonia

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AU - Richards, Lori

AU - Rajapaska, Amanda

AU - Hebb, Jonathan

AU - Chester, Cariad

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AU - Ostashko, Anton

AU - Weng, Wen Kai

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AU - Fu, Yang Xin

AU - Sunwoo, John

AU - Levy, Ronald

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