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.
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.
|Liu, Zhuqing; McMichael, Elizabeth L; Shayan, Gulidanna et al. (2018) Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients. Clin Cancer Res 24:4529-4538|
|Lu, Shanhong; Concha-Benavente, Fernando; Shayan, Gulidanna et al. (2018) STING activation enhances cetuximab-mediated NK cell activation and DC maturation and correlates with HPV+ status in head and neck cancer. Oral Oncol 78:186-193|
|Srivastava, Raghvendra M; Trivedi, Sumita; Concha-Benavente, Fernando et al. (2017) CD137 Stimulation Enhances Cetuximab-Induced Natural Killer: Dendritic Cell Priming of Antitumor T-Cell Immunity in Patients with Head and Neck Cancer. Clin Cancer Res 23:707-716|
|Concha-Benavente, Fernando; Ferris, Robert L (2017) Oncogenic growth factor signaling mediating tumor escape from cellular immunity. Curr Opin Immunol 45:52-59|
|Kansy, Benjamin A; Concha-Benavente, Fernando; Srivastava, Raghvendra M et al. (2017) PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. Cancer Res 77:6353-6364|
|Albergotti, William G; Gooding, William E; Kubik, Mark W et al. (2017) Assessment of Surgical Learning Curves in Transoral Robotic Surgery for Squamous Cell Carcinoma of the Oropharynx. JAMA Otolaryngol Head Neck Surg 143:542-548|
|Jie, Hyun-Bae; Srivastava, Raghvendra M; Argiris, Athanassios et al. (2017) Increased PD-1+and TIM-3+TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients. Cancer Immunol Res 5:408-416|
|Mazorra, Zaima; Lavastida, Anabel; Concha-Benavente, Fernando et al. (2017) Nimotuzumab Induces NK Cell Activation, Cytotoxicity, Dendritic Cell Maturation and Expansion of EGFR-Specific T Cells in Head and Neck Cancer Patients. Front Pharmacol 8:382|
|Weidhaas, Joanne B; Harris, Jonathan; Schaue, Dörthe et al. (2017) The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 3:483-491|
|Kikuchi, Masahiro; Clump, David A; Srivastava, Raghvendra M et al. (2017) Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1 monoclonal antibody for assessing radiation-induced PD-L1 upregulation in head and neck cancer and melanoma. Oncoimmunology 6:e1329071|
Showing the most recent 10 out of 50 publications