Head and neck squamous cell carcinoma (HNSCC) is a lethal solid malignancy with 5 year survival estimates of approximately 50%, and is associated with a high rate of systemic immune impairment as well a evasion of a tumor specific immune response. Preclinical and clinical data have shown that PDE5 inhibitors (tadalafil) can be used to augment immune function in HNSCC patients through inhibition of the cancer-induced myeloid derived suppressor cells (MDSCs). Separate, independent clinical trials in HNSCC patients have shown that tadalafil 1) can be safely administered;2) reduces MDSCs function and numbers; 3) increases global systemic immunity;4) increases TlLs;and 5) is associated with an increase In tumor-specific immunity. Based on these data we hypothesize that PDE5 inhibitors may be employed to 1) inhibit cancer induced MDSCs and 2) can increase tumor-specific immune response when combined with conventional multi-modality therapies for advanced head and neck squamous cell carcinoma (HNSCC). To test this hypothesis, we will administer long acting PDE5 inhibitors concurrently to HNSCC patients undergoing primary radiation therapy +/-chemotherapy, continuously during and after completion of therapy. We will assess 1) MDSC number and function, 2) immune response to vaccine, and 3) tumor-specific immunity at timepoints before, during, and after therapy to determine optimum timing and design of PDE5 immunotherapy in conjunction with conventional therapy for HNSCC. The long term goal ofthis project is to investigate and develop PDE5 inhibitors as safe, well tolerated immune modulators that improve tumor specific immune response in combination with conventional therapy. This approach may also be further developed as a potential adjunct to other immune based therapies, including vaccine based approaches in HPV positive HNSCC (Project 4) and novel combination antibody based therapies (Project 3).
Development of PDE5 inhibitors as safe, well tolerated immune modulators that improve tumor specific immune response in combination with conventional therapy may also integrated with other immune based therapies developed within the head and neck SPORE.
|Thompson, Elizabeth D; Stelow, Edward B; Mills, Stacey E et al. (2016) Large Cell Neuroendocrine Carcinoma of the Head and Neck: A Clinicopathologic Series of 10 Cases With an Emphasis on HPV Status. Am J Surg Pathol 40:471-8|
|Guo, Theresa; Rettig, Eleni; Fakhry, Carole (2016) Understanding the impact of survival and human papillomavirus tumor status on timing of recurrence in oropharyngeal squamous cell carcinoma. Oral Oncol 52:97-103|
|Stansfield, John C; Rusay, Matthew; Shan, Roger et al. (2016) Toward Signaling-Driven Biomarkers Immune to Normal Tissue Contamination. Cancer Inform 15:15-21|
|Kang, Hyunseok; Tan, Marietta; Bishop, Justin A et al. (2016) Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma. Clin Cancer Res :|
|Motz, Kevin; Qualliotine, Jesse R; Rettig, Eleni et al. (2016) Changes in Unknown Primary Squamous Cell Carcinoma of the Head and Neck at Initial Presentation in the Era of Human Papillomavirus. JAMA Otolaryngol Head Neck Surg 142:223-8|
|Guo, Theresa; Eisele, David W; Fakhry, Carole (2016) The potential impact of prophylactic human papillomavirus vaccination on oropharyngeal cancer. Cancer 122:2313-23|
|Walline, Heather M; Carey, Thomas E; Goudsmit, Christine M et al. (2016) High-Risk HPV, Biomarkers, and Outcome in Matched Cohorts of Head and Neck Cancer Patients Positive and Negative for HIV. Mol Cancer Res :|
|Rettig, Eleni M; Talbot Jr, C Conover; Sausen, Mark et al. (2016) Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma. Cancer Prev Res (Phila) 9:265-74|
|Sun, Yun-Yan; Peng, Shiwen; Han, Liping et al. (2016) Local HPV Recombinant Vaccinia Boost Following Priming with an HPV DNA Vaccine Enhances Local HPV-Specific CD8+ T-cell-Mediated Tumor Control in the Genital Tract. Clin Cancer Res 22:657-69|
|Fakhry, Carole; Qualliotine, Jesse R; Zhang, Zhe et al. (2016) Serum Antibodies to HPV16 Early Proteins Warrant Investigation as Potential Biomarkers for Risk Stratification and Recurrence of HPV-Associated Oropharyngeal Cancer. Cancer Prev Res (Phila) 9:135-41|
Showing the most recent 10 out of 109 publications