CD137 Stimulation Enhances Cetuximab-Induced Natural
Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with
Head and Neck Cancer
Srivastava RM1, Trivedi S1, Concha-Benavente
F2, Gibson SP1, Reeder C1, Ferrone S3, Ferris RL4,2,5.
1. Department of Otolaryngology,
University of Pittsburgh, Pittsburgh, Pennsylvania.
2. Department of Immunology,
University of Pittsburgh, Pittsburgh, Pennsylvania.
3. Department of Surgery,
Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
4. Department of Otolaryngology,
University of Pittsburgh, Pittsburgh, Pennsylvania. ferrisrl@upmc.edu.
5. Cancer Immunology Program,
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
Abstract
PURPOSE:
Cetuximab, an EGFR-specific
antibody (mAb), modestly improves clinical outcome in patients with head and
neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell
(DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing
antitumor cellular immunity. Cetuximab-activated NK cells upregulate the
costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb
urelumab, might enhance NK-cell functions, to promote T-cell-based immunity.
EXPERIMENTAL DESIGN:
CD137 expression on
tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab
neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in
combining agonistic urelumab with cetuximab. Flow cytometry and cytokine
release assays using NK cells and DC were used in vitro, testing the addition
of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells.
RESULTS:
CD137 agonist mAb urelumab enhanced
cetuximab-activated NK-cell survival, DC maturation, and tumor antigen
cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR,
and antigen-processing machinery (APM) components TAP1/2, leading to increased
tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients
with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells
correlated with FcγRIIIa V/F polymorphism and predicted clinical response.
Moreover, immune biomarker modulation was observed in an open label, phase Ib
clinical trial, of patients with HNC treated with cetuximab plus urelumab.
CONCLUSIONS:
These results suggest a
beneficial effect of combination immunotherapy using cetuximab and CD137
agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR.
Clin Cancer Res. 2017 Feb
1;23(3):707-716. doi: 10.1158/1078-0432.CCR-16-0879. Epub 2016 Aug 5.
Md. PhD. Fernando
Concha. Ex-miembro del GII
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