Immunotherapy in head and neck cancer – evaluation of sensitivity and mechanisms of resistance in patients treated with immune checkpoint inhibitors

• Applicant: Professor Dr. Maximilian Linxweiler
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: from 2018 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406319565

Head and neck squamous cell carcinomas (HNSCC) belong to the six most common cancers and are associated with a worse prognosis that has not significantly changed over the past decades. Recently, the blockade of so called immune checkpoints by therapeutic antibodies was introduced as a further treatment option for patients with recurrent or metastatic HNSCC and showed promising results in clinical trials. Unfortunately, the majority of tumors shows no significant clinical response or develops mechanisms of resistance over time. Therefore, the patients showing no response to immune checkpoint blockade remain a big challenge for clinical therapy of head and neck cancer with so far no effective treatment option in that devastating disease. Against this background, it is the goal of our study to gain insight into evolutionary processes of the tumor genome and the immunological tumor microenvironment during immune checkpoint blockade by analyzing HNSCC tissue samples that were gained at different time points during immunotherapy and, thereby, identify potential mechanisms of resistance as well as adopt and optimize therapy. Therefore, we will analyze pre- and posttherapeutic tissue samples from 60 HNSCC patients that received a neoadjuvant treatment at the Memorial Sloan Kettering Cancer Center (New York City, NY, USA) with immune checkpoint blockade in clinical trials using whole genome, RNA and T cell receptor (TCR) sequencing as well as custom mass cytometry panel analysis (CyTOF) in order to evaluate dynamic changes in (i) mutation and neoantigen load, (ii) mutation and neoantigen clonality, (iii) signal pathways with potential relevance for tumor immunogenicity and (iv) tumor infiltrating immune cells in sensitive and resistant tumors. Through this, we intend to identify immunotherapeutic vulnerabilities in HNSCC patients, uncovering the mechanisms of immune escape and adopted resistance against checkpoint blockade and finally improving therapeutic options and prognosis for HNSCC patients.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Luc Morris, Ph.D.