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.
|Pai, Sara I; Jack Lee, J; Carey, Thomas E et al. (2018) HLA class I antigen processing machinery (APM) component expression and PD-1:PD-L1 pathway activation in HIV-infected head and neck cancers. Oral Oncol 77:92-97|
|Bishop, Justin A; Rooper, Lisa M; Chiosea, Simion I et al. (2018) Clear Cell Carcinoma of Salivary Glands Is Frequently p16 Positive: A Pitfall in the Interpretation of Oropharyngeal Biopsies. Am J Surg Pathol 42:367-371|
|Afsari, Bahman; Guo, Theresa; Considine, Michael et al. (2018) Splice Expression Variation Analysis (SEVA) for inter-tumor heterogeneity of gene isoform usage in cancer. Bioinformatics 34:1859-1867|
|Bishop, Justin A; Cowan, Morgan L; Shum, Chung H et al. (2018) MAML2 Rearrangements in Variant Forms of Mucoepidermoid Carcinoma: Ancillary Diagnostic Testing for the Ciliated and Warthin-like Variants. Am J Surg Pathol 42:130-136|
|Kelley, Dylan Z; Flam, Emily L; Guo, Theresa et al. (2018) Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma. Transl Res 202:109-119|
|Ghantous, Yasmine; Schussel, Juliana L; Brait, Mariana (2018) Tobacco and alcohol-induced epigenetic changes in oral carcinoma. Curr Opin Oncol 30:152-158|
|Gleber-Netto, Frederico O; Zhao, Mei; Trivedi, Sanchit et al. (2018) Distinct pattern of TP53 mutations in human immunodeficiency virus-related head and neck squamous cell carcinoma. Cancer 124:84-94|
|Kagohara, Luciane T; Stein-O'Brien, Genevieve L; Kelley, Dylan et al. (2018) Epigenetic regulation of gene expression in cancer: techniques, resources and analysis. Brief Funct Genomics 17:49-63|
|Windon, Melina J; D'Souza, Gypsyamber; Rettig, Eleni M et al. (2018) Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer 124:2993-2999|
|Ravi, Rajani; Noonan, Kimberly A; Pham, Vui et al. (2018) Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGF? enhance the efficacy of cancer immunotherapy. Nat Commun 9:741|
Showing the most recent 10 out of 137 publications