There is convincing clinical evidence that the epidermal growth factor receptor (EGFR)-specific monoclonal antibody (mAb), cetuximab, is effective therapy only for a subset of advanced head and neck squamous cell carcinoma (HNC). Thus, there is a need to understand why clinical responses vary between individuals. In contrast to EGFR tyrosine kinase inhibitors, the use of a mAb raises the potential that the immune system might play a role in this clinical activity. Also, since treatment of HNC cells with cetuximab does not induce significant apoptosis in vitro, anti-tumor effects in vivo may be due in part to additional factors, such as immune cell activation through antibody dependent cellular cytotoxicity (ADCC) mediated by natural killer (NK) cells and monocytes, through the constant fragment (Fc) domain of the mAb binding to polymorphic Fc? receptors (Fc?R). However, little is known about whether T cells contribute to mAb therapies or whether polymorphic Fc?Rs influence the induction of T cell responses. The frequent downregulation of HLA class I antigen processing machinery (APM) and expression of NK inhibitory molecules by HNC cells, may provide a mechanism of resistance to NK cell- and tumor antigen specific T cell lysis of HNC cells. Thus, we hypothesize that the cellular arm of the immune system plays an important role in mediating the anti-tumor effects of cetuximab. We have evidence that Fc?R polymorphisms at Fc?RIIa131R/H and FcRIII158V/F influence ADCC activity in PBMC of healthy donors and HNC patients, and these codons also correlate with outcome of colorectal cancer patients treated with single agent cetuximab. In addition, we have identified that TNF-a, IFN-?, MIP-1a, and MIP-1?, are consistently expressed in vitro in the supernatant of ADCC responding PBMC. Released from activated NK cells, these cytokines and chemokines are chemotactic for T cells and dendritic cells (DC) cells, suggesting a potential link between cetuximab-induced NK lysis and induction of TA-specific T cell induction. Understanding immune mediated mechanisms of these mAb is important: (i) to select the most appropriate patients for cetuximab therapy with greatest ability to mount immune activation, (ii) to enhance anti-tumor ADCC and T cell activity in order to increase responses in cetuximab-treated patients and (ii) to identify predictive immune biomarkers of biological and clinical responsiveness, such as Fc?R polymorphisms, cellular immunity and immune escape mechanisms. A HNC murine model with different levels of EGFR expression and lymphocytes, characterized by Fc?R genotype from HNC patients of different disease stage and in the presence or absence of chemoradiotherapy or NK inhibitory molecules expressed by the tumor, will be used to test the hypothesis that PBMC expressing certain Fc?R genotypes or from advanced HNC patients influences antitumor activity. In addition we will determine whether cetuximab enhances antigen specific T cell induction by DC maturation and cross-presentation, which is influenced by Fc?R polymorphisms, cetuximab and NK cells. Lastly we propose to determine the effect of cetuximab responsiveness in HNC patients on NK and T cell activation, tumor infiltration, and defects in APM expression in HNC specimens from a phase II, single agent cetuximab clinical trial (08-013) at the University of Pittsburgh.

Public Health Relevance

Convincing evidence indicates that immunotherapy with the EGFR-specific monoclonal antibody (mAb) cetuximab is effective in the treatment of advanced head and neck squamous cell carcinoma (HNC), but in only 20% of the treated patients. The mechanism(s) underlying the differential clinical response to cetuximab-based immunotherapy are not known. The lack of this information has negative impact on the development of strategies to optimize cetuximab-based immunotherapy and the selection of patients to be treated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
3R01DE019727-04S1
Application #
8705630
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Venkatachalam, Sundaresan
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$178,136
Indirect Cost
$58,136
Name
University of Pittsburgh
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Trivedi, Sumita; Rosen, Clark A; Ferris, Robert L (2016) Current understanding of the tumor microenvironment of laryngeal dysplasia and progression to invasive cancer. Curr Opin Otolaryngol Head Neck Surg 24:121-7
Srivastava, Raghvendra M; Trivedi, Sumita; Concha-Benavente, Fernando et al. (2016) CD137 stimulation enhances cetuximab induced natural killer (NK): dendritic cell (DC) priming of anti-tumor T cell immunity in head and neck cancer patients. Clin Cancer Res :
Garcia-Bates, Tatiana M; Kim, Eun; Concha-Benavente, Fernando et al. (2016) Enhanced Cytotoxic CD8 T Cell Priming Using Dendritic Cell-Expressing Human Papillomavirus-16 E6/E7-p16INK4 Fusion Protein with Sequenced Anti-Programmed Death-1. J Immunol 196:2870-8
Trivedi, Sumita; Srivastava, Raghvendra M; Concha-Benavente, Fernando et al. (2016) Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients. Clin Cancer Res 22:5229-5237
Concha-Benavente, Fernando; Srivastava, Raghvendra M; Trivedi, Sumita et al. (2016) Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer. Cancer Res 76:1031-43
Jie, Hyun-Bae; Schuler, Patrick J; Lee, Steve C et al. (2015) CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis. Cancer Res 75:2200-10
Schmitt, Nicole C; Trivedi, Sumita; Ferris, Robert L (2015) STAT1 Activation Is Enhanced by Cisplatin and Variably Affected by EGFR Inhibition in HNSCC Cells. Mol Cancer Ther 14:2103-11
Jimeno, Antonio; Bauman, Julie E; Weissman, Charles et al. (2015) A randomized, phase 2 trial of docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. Oral Oncol 51:383-8
Li, Jing; Srivastava, Raghvendra M; Ettyreddy, Abhinav et al. (2015) Cetuximab ameliorates suppressive phenotypes of myeloid antigen presenting cells in head and neck cancer patients. J Immunother Cancer 3:54
Srivastava, Raghvendra M; Trivedi, Sumita; Concha-Benavente, Fernando et al. (2015) STAT1-Induced HLA Class I Upregulation Enhances Immunogenicity and Clinical Response to Anti-EGFR mAb Cetuximab Therapy in HNC Patients. Cancer Immunol Res 3:936-45

Showing the most recent 10 out of 34 publications