Abstract A55: PD-1 blockade synergizes with cisplatin radiation therapy aiding in clearance of murine HPV+ oropharyngeal carcinoma

Abstract

Abstract Squamous cell carcinomas of the head and neck (SCCHN) are the 6th most common malignancy world-wide with approximately 650,000 diagnoses per year. Human papillomavirus (HPV) causes up to 80% of oropharyngeal (tonsil/base of tongue) SCCHN. Despite presenting at an advanced stage, multiple studies show that HPV+ SCCHN are more curable relative to their HPV- counterparts. Clearance of SCCHN during treatment with cisplatin radiation therapy (CRT) is not only related to direct cytotoxicity, but is also dependent on immune mediated clearance. This immune clearance is strongly dependent on an intact CD4+ and CD8+ cellular response to tumor cells harboring these viral oncogenes. Furthermore, the immune system recognizes and clears HPV + SCCHN only after the start of CRT. The immunologic tolerance to these cancers prior to treatment could be explained by immune checkpoints aimed at preventing unregulated immune activity. The programmed death 1 receptor (PD-1) and its ligand, PD-L1, are one such checkpoint axis. Recent data suggests that the PD-1:PD-L1 pathway may play an important role in immune resistance in head and neck cancer. We evaluated PD-1 in combination with CRT in an immune competent HPV+ SCCHN mouse model. HPV + mouse SCCHN cells were injected subcutaneously into immune competent mice and tumors were treated after growing to palpable size. Using the mouse analog to the human PD-1 blocker, pembrolizumab, we determined that while single-agent therapy does not have significant activity on primary disease or distant metastasis, PD-1 blockade strongly synergizes with CRT. An overall survival of 58% was evident in mice treated with combination PD-1 and CRT versus 8% in mice treated with isotype control (IgG1) in combination with CRT (p = 0.006). These studies provide the impetus for future work investigating less toxic induction of immune responses in combination with blockade of immune checkpoint pathways. Citation Format: Daniel W. Vermeer, Steven Powell, William C. Spanos, John H. Lee. PD-1 blockade synergizes with cisplatin radiation therapy aiding in clearance of murine HPV+ oropharyngeal carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A55.