Abstract
Abstract Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) treated with anti-EGFR (cetuximab) mAb-based immunotherapy often acquire therapy-resistance, reducing clinical benefit. We evaluated the efficacy of a combined modality in situ vaccination regimen aimed at overcoming resistance to cetuximab using a syngeneic tumor model. Experimental Design: The murine HNSCC cell line MOC2 was transduced to express human EGFR (MOC2-huEGFR) and used as a syngeneic model of therapeutic resistance to cetuximab. The cells were tested for viability, radiosensitivity, and huEGFR-specific mAb binding efficacy in the presence of cetuximab. Antibody-dependent cellular cytotoxicity (ADCC) was tested by coculture of 51chromium-labeld MOC2-huEGFR with PBMC. Mice bearing these syngeneic tumors were treated with therapeutic regimens that included local radiation (RT), intratumoral (IT) cetuximab, and/or systemic immune checkpoint inhibitors, and tumor growth/survival rate were monitored. Result: Cetuximab induced antibody-dependent cellular cytotoxicity (ADCC) in MOC2-huEGFR and PBMC co-cultures, but showed no effect on cell proliferation or radiosensitivity. Combined RT and IT-cetuximab treatment induced tumor growth delay, which required huEGFR expression, NK cells, and FcγR expression. In addition, combined RT+IT-cetuximab therapy greatly induced tumor infiltration by both CD8 T cells and NK cells. RT promoted NK cell-mediated ADCC effects against 51chromium-labeld MOC2-huEGFR with increased IFNγ expression. Proliferating tumor cells gradually increased Pd-l1 mRNA expression, and RT enhanced cell surface PD-L1 in MOC2-huEGFR cells. Systemic anti-PD-L1 antibody or IT-cetuximab alone did not show antitumor response against MOC2-huEGFR bearing mice; however, significant tumor growth inhibition was observed with combined anti-PD-L1, RT, and IT-cetuximab. Conclusion: The MOC2-huEGFR HNSCC tumor model is immunologically “cold” and does not respond to either cetuximab or anti-PD-L1 therapies alone. In this model, we show that a combination of RT+cetuximab+anti-PD-L1 elicits a cooperative in situ vaccine effect. Combining RT, cetuximab and immune checkpoint blockade may enable anti-tumor immune response in HNSCC patients with immunologically cold, huEGFR-expressing tumors. Citation Format: Wonjong Jin, Amy K. Erbe, Ciara Schwarz, Abigail Jaquish, Bryce R. Anderson, Raghava N. Sriramaneni, Justin C. Jagodinsky, Paul A. Clark, Zachary S. Morris. Immune mediated interaction between radiation and cetuximab in a syngeneic murine model of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1881.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have