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).

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Specialized Center (P50)
Project #
5P50DE019032-13
Application #
8703521
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
13
Fiscal Year
2014
Total Cost
$372,068
Indirect Cost
$135,636
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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
Bishop, Justin A; Westra, William H (2018) MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma: Evaluation of Classic, Variant, and Hybrid Forms. Am J Surg Pathol 42:319-325
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

Showing the most recent 10 out of 137 publications