Enhancing anti-tumor immunity in head and neck neoplasms

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Major activities of our program include progress in both HNSCC and RRP. Our recent work on HNSCC has focused on the rationale sequencing of immune checkpoint blockade (ICB) immunotherapy and surgery for patients with newly diagnosed HNSCC. Previous mouse work in our laboratory revealed that ICB resulted in the development of durable, systemic anti-tumor immunity when administered prior to surgical resection of tumors but not when the ICB was administered after surgery. This observation was striking, but the mechanisms underlying this finding were unclear. To study this phenomenon in patients, we designed and completed a phase II study of neoadjuvant ICB in patients with HNSCC and studying pre- and post-treatment tumor biopsies and blood samples. We observed that tumor-specific T cells became activated and expanded in the tumor after treatment. Additionally, we observed that tumors act as a reservoir for tumor-specific T cells through induction of a tissue residency gene expression program. With ICB treatment, a proportion of the tumor-specific T cells were released from the tumor into circulation, leading to enhanced systemic anti-tumor immunity. These data indicate that without neoadjuvant ICB treatment, most of a patient's anti-tumor immune response would be removed with surgical removal of the tumor. Conversely, neoadjuvant ICB induces egress of some T cells from the tumor, enhancing the patient's systemic immunity. These findings are the strongest scientific argument to date supporting the use of neoadjuvant ICB in patients with HNSCC. We next explored the mechanistic drivers of this tissue resident gene expression program in tumor-specific T cells in the laboratory and found TGF-b to be a major driver. In pre-clinical mouse studies, we observe that the addition of TGF-b blockade to ICB further enhanced the degree of systemic antitumor immunity that develops compared to ICB alone. Our ongoing work aims to determine if other pathways are involved in efforts to uncover more possible therapeutic strategies to enhance systemic anti-tumor immunity in patients with newly diagnosed HNSCC. Our recent work on RRP has focused on identifying non-surgical, medical treatment options for this rare, hard to treat disease. The standard-of-care treatment for RRP is repeat surgery to debulk disease and maintain a functional voice and airway. Our team has pioneered approaches to address the underlying cause of RRP, chronic HPV infection, with immunotherapy. Initial trials with immune checkpoint blockade (ICB) resulted in clinical benefit for some patients, but no patients were cured. Our correlative analyses on specimens from these trials revealed that ICB was not unleashing the activity of HPV-specific T cells in papillomas, due at least in part to the paucity of HPV-specific T cells present in these papillomas at baseline. We next worked with an industry partner to develop a therapeutic vaccine designed to generate new or expand existing HPV-specific T cells in patients with RRP. Phase I clinical study with this new vaccine resulted in robust clinical activity and protocol defined complete responses in 50% of patients. Correlative studies from this trial revealed significant, polyclonal expansion of HPV-specific T cells in the periphery after vaccination and the ability of these T cells to traffic and infiltrate into papillomas in responder patients. Ongoing phase II study with this vaccine has led to FDA Breakthrough Designation. These data indicated that enhancement of peripheral HPV-specific T cell immunity can lead to papilloma destruction and clinical benefit in patients with HPV-driven neoplasms. Yet, therapeutic vaccination does not result in the expansion peripheral HPV-specific T cell immunity in all patients. Other approaches are needed to enhance systemic HPV-specific immunity in these patients. Adoptive transfer of autologous T cells engineered to express a T cell receptor (TCR) specific for HPV has proven efficacy in HPV-associated malignancies and could be a new approach for life-threatening cases of RRP. Treatment with chimeric antigen receptor (CAR) T cells is not possible currently as no cell surface markers specific for HPV infected papilloma cells are known. A TCR-engineered T cell therapy approach necessitates the discovery of one or more TCRs that recognize antigen derived from HPV 6 or 11. Discovery of novel TCRs that target HPV 6 or 11 antigens is a major research effort currently in our laboratory.