IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells

Abstract

Purpose Alternative strategies to EGFR blockage by mAbs is necessary in order to improve the efficacy of therapy in patients with locally advanced or metastatic pancreatic cancer. One such strategy includes the use of NK cells to clear cetuximab-coated tumor cells, as need for novel therapeutic approaches to enhance the efficacy of cetuximab is evident. We show that IL-21 enhances NK cell-mediated effector functions against cetuximab-coated pancreatic tumor cells irrespective of KRAS mutation status. Experimental Design NK cells from normal donors or donors with pancreatic cancer were used to assess ADCC, IFN-γ release, and T cell chemotaxis towards human pancreatic cancer cell lines. The in vivo efficacy of IL-21 in combination with cetuximab was evaluated in a subcutaneous and intraperitoneal model of pancreatic cancer. Results NK cell lysis of cetuximab-coated wild-type and mutant KRAS pancreatic cancer cell lines was significantly higher following NK cell IL-21 treatment. In response to cetuximab-coated pancreatic tumor cells, IL-21 treated NK cells secreted significantly higher levels of IFN-γ and chemokines, increased chemotaxis of T cells, and enhanced NK cell signal transduction via activation of ERK and STAT1. Treatment of mice bearing subcutaneous or intraperitoneal EGFR-positive pancreatic tumor xenografts with mIL-21 and cetuximab led to significant inhibition of tumor growth, a result further enhanced by the addition of gemcitabine. Conclusions These results suggest that cetuximab treatment in combination with IL-21 adjuvant therapy in patients with EGFR-positive pancreatic cancer results in significant NK cell activation, irrespective of KRAS mutation status, and may be a potential therapeutic strategy.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Accordingly, treatments incorporating anti-CTLA-4 mAbs or transient Treg depletion could potentially increase efficacy (195). Cetuximab in conjunction with toll-like receptor agonists, PD-1 blockade, and CD137 agonists, may also enhance efficacy, in addition to cytokine administration (69,181,182,(196)(197)(198)(199)(200). Moreover, combination treatment with super agonist cytokines (discussed below) may substantially potentiate Cetuximab activity, as recently described for the IL-15 super agonist ALT-803 (201).…”

“…Cetuximab, is an anti-EGFR mAb used clinically for cancer treatment. Cetuximab can activate NK cell ADCC in-vitro and in-vivo, and initiate an adaptive immune response through activation of NK cell:DC crosstalk (180)(181)(182). Ex-vivo stimulation of NK cell ADCC with Cetuximab may also be predictive of clinical responses in patients (183).…”

Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma

“…The hypothesis that the antitumor effects of cetuximab are driven by immune mechanisms is supported by a number of lines of evidence, including that lymphocytes are necessary for cetuximab to induce tumor killing in vitro and that cetuximab's effects are influenced by Fcγ receptors present on natural killer (NK) cells . Work done by our lab and others supports the hypothesis that NK cells mediate cetuximab's antitumor effects via antibody‐dependent cellular cytotoxicity (ADCC) and through upregulation of EGFR‐specific CTL via NK: dendritic cell (DC) crosstalk. NK‐dependent ADCC is mediated by binding of FcγRIIIa (CD16) to the Fc portion of cetuximab‐coated EGFR+ tumor cells.…”

Antibody‐dependent cell cytotoxicity: immunotherapy strategies enhancing effector NK cells

“…Preclinical reports indicated that IL‐21 enhances NK cell‐mediated ADCC 63 and, in a phase I clinical trial administering IL‐21 and cetuximab to metastatic colorectal cancer patients, IL‐21 showed good tolerability and a post‐treatment increased expression of CD25 on T and NK cells 64 . IL‐21 is now being tested in a number of clinical trials with different anti‐TAA mAb 65 and is considered a promising cytokine to increase T‐cell and NK cell activity in patients.…”