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.
|Li, Ryan; Faden, Daniel L; Fakhry, Carole et al. (2015) Clinical, genomic, and metagenomic characterization of oral tongue squamous cell carcinoma in patients who do not smoke. Head Neck 37:1642-9|
|Gaykalova, Daria A; Mambo, Elizabeth; Choudhary, Ashish et al. (2014) Novel insight into mutational landscape of head and neck squamous cell carcinoma. PLoS One 9:e93102|
|Dýýsouza, Gypsyamber; Carey, Thomas E; William Jr, William N et al. (2014) Epidemiology of head and neck squamous cell cancer among HIV-infected patients. J Acquir Immune Defic Syndr 65:603-10|
|Wu, Chao-Yi; Yang, Li-Hua; Yang, Huang-Yu et al. (2014) Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors. Clin Cancer Res 20:644-57|
|Bishop, Justin A; Yonescu, Raluca; Batista, Denise et al. (2014) Mucoepidermoid carcinoma does not harbor transcriptionally active high risk human papillomavirus even in the absence of the MAML2 translocation. Head Neck Pathol 8:298-302|
|Sun, Wenyue; Gaykalova, Daria A; Ochs, Michael F et al. (2014) Activation of the NOTCH pathway in head and neck cancer. Cancer Res 74:1091-104|
|Fakhry, Carole; Gillison, Maura L; D'Souza, Gypsyamber (2014) Tobacco use and oral HPV-16 infection. JAMA 312:1465-7|
|Izumchenko, Evgeny; Chang, Xiaofei; Michailidi, Christina et al. (2014) The TGF?-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res 74:3995-4005|
|Bishop, Justin A; Yonescu, Raluca; Batista, Denise et al. (2014) Glandular odontogenic cysts (GOCs) lack MAML2 rearrangements: a finding to discredit the putative nature of GOC as a precursor to central mucoepidermoid carcinoma. Head Neck Pathol 8:287-90|
|Bishop, Justin A; Antonescu, Cristina R; Westra, William H (2014) SMARCB1 (INI-1)-deficient carcinomas of the sinonasal tract. Am J Surg Pathol 38:1282-9|
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