Targeting CD137 enhances the efficacy of cetuximab

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2014-06, Vol.124 (6), p.2668-2682
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal, Humanized - administration & dosage
Antibody-Dependent Cell Cytotoxicity
Antigens
Antineoplastic Agents - administration & dosage
Biomedical research
Breast cancer
Cancer
Cancer cells
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Cetuximab
Colorectal Neoplasms - genetics
Colorectal Neoplasms - immunology
Colorectal Neoplasms - therapy
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - metabolism
Female
Gene expression
Genetic aspects
Head and Neck Neoplasms - genetics
Head and Neck Neoplasms - immunology
Head and Neck Neoplasms - therapy
Humans
Immune response
Immune system
Immunotherapy, Adoptive
Killer Cells, Natural - immunology
Kinases
Life Sciences
Medical research
Mice
Mice, Inbred BALB C
Mice, Nude
Mutation
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins p21(ras)
ras Proteins - genetics
Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors
Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism
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Description
Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI73014