Enhancing anti-tumor immunity in head and neck neoplasms

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Project 1: Optimize anti-tumor immunity with neoadjuvant immunotherapy for oral cavity cancers Background: Oral squamous cell carcinoma (OSCC), typically caused by carcinogen exposure, carries a poor prognosis. Roughly half of all patients with newly-diagnosed advanced stage OSCC will relapse in two years despite receiving maximal treatment consisting of disfiguring surgery and adjuvant radiotherapy with or without chemotherapy. Once disease recurs, few effective treatments exist. Treatment of unresectable locoregionally relapsed disease or distant metastasis with pembrolizumab (monoclonal antibody targeting programmed death receptor-1; PD-1) immune checkpoint blockade (ICB) alone or in combination with chemotherapy leads to objective responses in approximately 30% of patients and a modest increase in progression free survival. Escalation of definitive, upfront treatment of patients with newly-diagnosed advanced stage OSCC to improve recurrence free survival (RFS) is an unmet need to reduce the proportion of patients that develop disease relapse. Specific Research Aims: To study the primary hypothesis for this project, significant progress has been made on the following three specific research aims: Aim 1: Evaluate the clinical and scientific effects of neoadjuvant TGF-beta blockade plus ICB for OSCC. Aim 2: Develop strategies that minimize tumor clonal escape to maximize pathologic response for OSCC. Aim 3: Understand and alter the function of immunosuppressive neutrophils in newly diagnosed OSCC. Project 2: Establish risk-stratified treatment approaches for patients with newly diagnosed HPV-related oropharyngeal cancer Background: HPV-associated oropharyngeal SCC (HPV-OPSCC) etiologically linked to chronic infection with high-risk HPV (typically HPV 16) is a biologically distinct disease from OSCC. Standard of care treatment for newly diagnosed HPV-OPSCC in the United States consists of either concurrent chemo-radiation (CRT) or surgical resection followed by risk-adapted adjuvant radiation. Given that up to 90% of all patients that proceed straight to surgery require adjuvant radiation due to the presence of one or high-risk features on pathology, nearly all patients receive radiation28. These treatments are highly effective for patients with stage 1 or 2 disease with >80% 5-year survival rates, but radiation often causes long-term xerostomia, dysphagia, dysphonia and sometimes airway obstruction. Treatment de-escalation for appropriately selected stage 1 and 2 patients to preserve oncologic tumor control but minimize long-term toxicity is a focus of the field. Attempts at de-escalation to date have included modest reductions in radiation dose. Clinical studies have also unsuccessfully attempted to replace cisplatin with cetuximab for patients receiving CRT. An alternative de-intensification strategy is the neoadjuvant chemotherapy plus surgery (NAC+S, 3 cycles of cisplatin plus docetaxel) approach that has been utilized as 'standard of care' by a few North American institutions for nearly a decade. Retrospective, uncontrolled institutional case series detail observations of 5-year RFS rates of >90% with a very low proportion of patients requiring any adjuvant treatment due to brisk pathologic responses observed with NAC. Criticisms of this data are its uncontrolled nature having not been generated under prospective clinical trials with clear inclusion criteria and rigorous follow-up. If the safety and oncologic control of the NAC+S strategy alone or in combination with safe immunotherapy could be confirmed in a prospective, controlled trial, it could represent a significant treatment de-escalation option for patients with surgically resectable, newly diagnosed HPV-OPSCC that wish to try and avoid radiation treatment. Unlike early stage newly diagnosed HPV-OPSCC, 5-year survival drops to below 70% following standard of care treatment for patients with stage 3 disease. Disease relapse remains a significant problem and treatment escalation to improve RFS and reduce the proportion of patients that relapse is needed for this cohort of HPV-OPSCC patients. For the reasons mentioned above, safe immunotherapy administered prior to definitive treatment, in this case induction immunotherapy prior to CRT as the great majority of these patients are considered surgically unresectable, is a rationale strategy to try to improve RFS. Specific Research Aims: Across disease stages, the presence of viral (HPV) antigens in the cells of these newly-diagnosed HPV-OPSCC tumors provides an opportunity to leverage HPV-specific immunotherapy to boost anti-tumor immunity. Through execution of the following specific aims, our program aims to study neoadjuvant or induction immunotherapy-based strategies that will inform future de-escalated treatment strategies for patients with newly diagnosed stage 1 and 2 surgically resectable HPV-OPSCC and escalated treatment strategies for patients with newly diagnosed stage 3 surgically unresectable HPV-OPSCC: Aim 1: Execute study of induction HPV therapeutic vaccination alone or in combination with pembrolizumab in patients with newly diagnosed p16-positive OPSCC. Aim 2: Execute study of NAC alone or in combination with HPV therapeutic vaccination prior to resection in patients with newly diagnosed stage 1 or 2 HPV-OPSCC. Project 3: Design and implement novel immunotherapeutic treatment strategies for recurrent respiratory papillomatosis Background: Recurrent respiratory papillomatosis (RRP) is a debilitating disorder caused by chronic infection with HPV type 6 or 11 that manifests as recurrent mucosal papillomas in the pharynx, larynx and trachea resulting in profound dysphonia and airway obstruction. In addition to these medical issues, chronic dysphonia results in social isolation, avoidance of career and social activities, and financial toxicity due to care-related expenses. Although the incidence of pediatric RRP cases is declining due to increased penetrance of preventative vaccination, incidence of adult RRP in non-vaccinated individuals is not declining and RRP remains a dominant and difficult to treat problem for Otolaryngologists. No approved medical treatments exist for RRP. Specific Research Aims: We hypothesized that HPV-specific immunotherapy or other systemic treatments could safely lead to durable disease control in adult patients with RRP. To study this hypothesis, significant progress has been made on the following three specific research aims: Aim 1: Develop a therapeutic vaccine to enhance HPV6/11-specific T cells in patients with RRP. Aim 2: Execute a prospective clinical trial of systemic bevacizumab for adults in RRP. Aim 3: Discover HPV6/11-specific T cell receptors (TCRs) for possible use in engineered cell therapy for RRP.