The approach that we have taken to this area of translational research is to develop various novel immunodulatory therapies which targets the spectrum of head and neck cancer care, which includes the recurrent and/or metastatic, newly diagnosed, and the pre-malignant setting.  Some active areas of research for these different stages of cancer include:

Our laboratory seeks to investigate the tumor immune microenvironment of HPV-associated head and neck cancers in the context of PD-1:PD-L1 pathway activation with a goal of identifying additional targetable pathways for clinical translation. We validate the identified targets in a larger cohort of patient samples as well as assess the impact of targeted blockade alone and in combination with anti-PD1 in pre-clinical cancer models which assists in informing the appropriate targets for translation into head and neck cancer patients.

Our translational research interest to identify and overcome mechanisms of immune resistance in head and neck cancer is the major focus of a program project (P01) grant. The goal of our P01 grant is to build upon the incremental successes of immunotherapy and improve clinical outcomes by addressing two main barriers to achieving clinical response to immunotherapy: (a) the tumor’s overall poor antigenicity (intrinsic mechanism), which limits the generation of antitumor immunity, and (b) innate and adaptive immune suppression (extrinsic mechanism) that results in immune tolerance. One specific projectfocuses on reprogramming the antigenicity of head and neck cancers through epigenetic therapy with the goal of enhancing overall tumor antigen presentation and recognition by the immune system. We hypothesize that a DNA methyltransferase inhibitor can uncover epigenetically silenced genes, such as HLA class I antigen processing machinery (APM) components and neo-antigens across and within heterogeneous tumor cell populations, to uniformly improve tumor cell antigenicity and, thus, immunogenicity which can translate into clinical benefit.  This hypothesis is being evaluated in an ongoing phase 1 clinical trial (NCT 03019003).

In addition, our group is assessing whether a novel immunomodulatory fusion protein, CUE-101, can increase the frequency and function of tumor infiltrating HPV-16 specific T cells. The backbone of CUE-101 is the Immuno-STAT (Selective Targeting and Alteration of T cells) platform that utilizes a modular framework that consists of an interchangeable HLA complex with an interchangeable bound tumor-associated antigen (TAA) peptide epitope. In addition, through enzymatic linkers, the fusion protein can locally deliver any cytokine(s), ligand(s), and/or co-stimulatory molecule to directly stimulate and activate tumor-specific T cells in vivo. Therefore, we are investigating directly in human subjects whether the CUE-101 platform, either alone or in combination with pembrolizumab, is able to reinvigorate pre-existing systemic and/or local HPV-(or tumor)-specific immune responses as well as induce memory HPV-specific T cells which can translate into prolonged disease free survival (DFS) (NCT 03978689).

We have an ongoing therapeutic clinical trial administering immunotherapy to patients with pre-malignant tumors. Recurrent Respiratory Papillomatosis (RPP) is caused by infection with human papillomavirus (HPV) types 6 and 11 and is characterized by mucosal tumors that grow in the respiratory tract, impacting breathing, swallowing, and speech. In 3-5% of patients, the lesions can undergo malignant transformation and the prognosis for patients who develop cancers derived from their RRP is poor due to the limited treatment options available. There is no effective systemic therapy for RRP, despite the fact that it typically involves multiple anatomic subsites. Thus, there is a strong unmet clinical need to develop novel treatment options for RRP patients. We and others have shown that RPP is a disease characterized by an ineffective host immune response to HPV, in part, through the upregulation of the PD1:PDL1 axis. Thus, we hypothesized that administration of a blocking PD-1 monoclonal antibody, pembrolizumab, can re-activate host anti-tumor responses, leading to the regression of existing RPP lesions, clearance of chronic HPV infection, and prevention of new disease as a means to improve the quality of life and achieve possible cure. To test this hypothesis, we opened an investigator-initiated phase II clinical trial administering pembrolizumab to subjects diagnosed with advanced RRP (DFHCC IRB#15-469; NCT02632344) to evaluate the effectiveness of immunotherapy as a novel treatment option. We have completed up to 2-years of treatment of all patients in January 2021 and we are currently analyzing the serial peripheral blood and tumor biopsy samples obtained from each treated patient.  Utilizing RNASequencing, proteomic microarrays, HPV tetramer staining followed by flow cytometry, and multiplex immunofluorsecence staining, we are assessing HPV-specific T cell modulation with long term treatment with immunotherapy.

Given the unprecedented growth in biotechnology and pharmaceutical drug development in the past 10 years surrounding IO drugs, both clinicians and patients are overwhelmed with the multitude of currently available treatment options. Thus, there are increasing efforts to discover and integrate predictive and/or prognostic biomarkers into treatment algorithms in order to optimize cancer care (Pai SI et al J Immunother Cancer 2020). Over the next 5-10 years, this is the area of greatest potential growth and clinical impact in the IO field which is the rationale for it being the second major focus of our translational research efforts. Utilizing scRNAseq, genomics, mouse models and human tissue, we have ongoing collaborative efforts to identify and prospectively validate new diagnostic and predictive biomarkers of response to immunotherapy in a variety of cancers.