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About this Laboratory
The Head and Neck Translational Immuno-Oncology Research Laboratory at Massachusetts General Hospital focuses on two areas:
- The development of novel immunomodulatory therapies for head and neck cancer patients
- The discovery and clinical application of diagnostic and/or predictive biomarkers
Development of Novel Immunomodulatory Therapies for Head and Neck Cancer Patients
Our approach to this area of translational research is to develop various novel immunomodulatory therapies that target the spectrum of head and neck cancer care, including in the recurrent or metastatic, newly diagnosed and pre-malignant setting.
Active areas of research for these different stages of cancer:
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Patients
Our team seeks to investigate the tumor immune microenvironment of human papillomavirus (HPV)-associated head and neck cancers in the context of PD-1/PD-L1 pathway activation to identify additional targetable immune checkpoint pathways for clinical translation. We validate the identified targets in a cohort of patient samples as well as assess the impact of targeted blockade, alone and in combination with anti-PD-1, in preclinical cancer models, which assists in informing the appropriate targets for translation into head and neck cancer patients as early phase clinical trials.
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:
- The tumor’s overall poor antigenicity (intrinsic mechanism), which limits the generation of antitumor immunity
- Innate and adaptive immune suppression (extrinsic mechanism) that results in immune tolerance
Pre-Malignant HPV-associated Recurrent Respiratory Papillomatosis
We have also completed a therapeutic clinical trial administering pembrolizumab to patients with pre-malignant tumors. Recurrent respiratory papillomatosis (RRP) is caused by infection with 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 sites. Thus, there is a strong unmet clinical need to develop novel treatment options for patients with RRP.
We and others have shown that RRP is a disease characterized by an ineffective host immune response to HPV, in part through the upregulation of the PD-1/PD-L1 axis. Thus, we hypothesized that administration of a blocking PD-1 monoclonal antibody, pembrolizumab, can re-activate host antitumor responses, leading to the:
- Regression of existing RRP lesions
- Clearance of chronic HPV infection
- 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 patients diagnosed with advanced RRP (DFHCC IRB#15-469; NCT02632344) to evaluate the effectiveness of immunotherapy as a novel treatment option. In January 2021, we completed treatment of all patients. The preliminary results have been presented at the American Society of Clinical Oncology annual meetings in 2019 and 2021. We are preparing a manuscript reporting our final clinical trial results.
Discovery and Clinical Application of Diagnostic and Predictive Biomarkers
Given the unprecedented growth in biotechnology and pharmaceutical drug development in the past 10 years surrounding novel immunomodulatory 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 prognostic biomarkers into treatment algorithms in order to optimize cancer care (Pai SI et al., J Immunother Cancer, 2020).
Utilizing single-cell RNA sequencing, 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.
- Mattox AK, Roelands J, Saal T, Cheng Y, Rinchai D, Hendrickx W, Young GD, Diefenbach T, Berger AE, Westra WH, Bishop JA, Faquin WC, Marincola FM, Pittet MJ, Bedognetti D, Pai SI. Myeloid cells are enriched in tonsillar crypts providing insight into the host tropism of HPV. Am J Pathology. 2021, in press.
- Oh J, Carlson JCT, Landeros C, Lee H, Ferguson S, Faquin WC, Clark JR, Pittet MJ, Pai SI, Weissleder R. Rapid serial immunoprofiling of the tumor immune microenvironment by fine needle sampling. Clin Cancer Res. 2021, in press.
- Pai SI, Faquin WC, Sadow PM, Pittet MJ, Weissleder R. New technology on the horizon: FAST-FNA enables rapid, multiplex biomarker analysis in head and neck cancers. Cancer Cytopath. 2020 Nov;128(11):782-791. PMID: 32841527.
- Mahmood U, Bang A, Chen HY, Mak RH, Lorch JH, Hanna GJ, Nishino M, Manuszak C, Thrash EM, Severgnini M, Sanborn M, Sridharan V, Margalit DN, Tishler RB, Busse PM, Willers H, Mamon HJ, Yoo HJ, Pai SI, Wirth LJ, Haddad RI, Chau NG, Schoenfeld JD. A randomized phase II study of pembrolizumab with or without radiation in patients with recurrent or metastatic adenoid cystic carcinoma. Inter J Radiat Oncol Biol Phys. 2020 Aug 8; S0360-3016 (20)43106-7. PMID: 32781104.
- Millar DG, Ramjiawan RR, Kawaguchi K, Gupta N, Chen J, Zhang S, Nojiri T, Ho WW, Aoki S, Jung K, Chen I, Shi F, Heather JM, Shigeta K, Morton LT, Sepulveda S, Wan L, Joseph R, Minogue E, Khatri A, Bardia A, Ellisen LW, Corcoran RB, Hata A, Pai SI, Jain RK, Fukumura D, Duda DG, Cobbold M. Antibody-mediated delivery of viral epitopes to tumors harnesses CMV-specific T cells for cancer therapy. Nat Biotech. 2020 Apr;38(4):420-425. PMID: 32042168.
- Pai S, Blaisdell D, Brodie R, Carlson R, Finnes H, Galioto M, Jensen RE, Valuck T, Sepulveda AR, Kaufman HL. Defining current gaps in quality measures for cancer immunotherapy: consensus report from the Society for Immunotherapy of Cancer (SITC) 2019 Quality Summit. J Immunother Cancer. 2020 Jan; 8(1). Pii: e000112. Coi: 10.1136. PMID: 31949040.
- Pai SI, Cohen EEW, Lin D, Foutzilas G, Kim ES, Mehlhorn H, Baste N, Clayburgh D, Lipworth L, Resteghini C, Shara N, Fuji T, Zhang J, Stokes M, Wang H, Twumasi-Ankrah P, Wildsmith S, Khaliq A, Melilo G, Shire N. SUPREME-HN: A retrospective biomarker study assessing the prognostic value of PD-L1 expression in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Transl Med. 2019 Dec 26; 17(1):429. PMID: 31878938.