Please refer to section 5.1 for details. Biopsies of tumor, normal mucosa and skin: This pre-treatment biopsy is mandatory. Whenever possible, this will be done with local anesthesia in the clinic. When tumor is not safely accessible in the clinic, procedure will be done under general anesthesia in the operating room. If general anesthesia is required to biopsy the tumor, the normal mucosa and skin biopsies will be done under general anesthesia as well. Regional metastasis in the cervical lymph nodes may be sampled via core biopsies guided by bimanual palpation or ultrasound. Clinic-based flexible nasopharyngo-laryngoscopy and/or tracheoscopy 26 Abbreviated Title: Neoadjuvant IO for HNSCC Version Date: August 31, 2022 3 STUDY IMPLEMENTATION 3.1 STUDY DESIGN This protocol is a window of opportunity neoadjuvant immunotherapy study. After obtaining pre-treatment biopsies, imaging and blood collection, patients will receive the neoadjuvant immunotherapy at the NIH Clinical Center. Patients will receive investigational immunotherapy on days 1 and 15, during the four to five-week period of time when patients have scheduled and are awaiting definitive surgery. Patients will then be taken off treatment on day 21-28 and post- treatment imaging and blood collection will be performed at the NIH Clinical Center. Patients will then be sent back to their referring providers for their definitive standard of care surgery and adjuvant therapy as indicated based upon pathologic analysis of the surgical specimen. At outside institutions, surgery and adjuvant treatment will be performed and chosen solely by outside providers. NCI investigators will have no role in surgery or adjuvant treatments received at outside institutions. In some cases, standard of care surgery may be offered at the NIH Clinical Center under a separate NIDCD protocol (01-DC-0099). This protocol treats patients with neoadjuvant immunotherapy only; standard of care surgery and any indicated adjuvant therapy is not part of this protocol. Tissue blocks or slides from surgically resected tissues will be obtained from these outside institutions and reviewed by the Laboratory of Pathology to determine primary outcome measures. Secondary clinical outcome measures will be determined by CT imaging and by following patients that are off treatment but receiving standard of care surgery and adjuvant therapy. Immune correlative analyses may be performed on pre- and post-treatment tissues (tumor, normal mucosa and skin) and bloods. Pre-treatment biopsies will be obtained in the clinic setting (OP5 Otolaryngology clinic) under local anesthesia only whenever possible. When not possible or safe to obtain biopsies in the clinic, biopsies will be obtained under general anesthesia in the operating room at the NIH Clinical Center. Post-treatment biopsies will be obtained at the time of standard of care surgery if the surgery is being performed at the NIH Clinical Center or at Suburban Hospital. If the surgery will be performed at an outside academic institution other than Suburban Hospital, then biopsies will be performed in the clinic setting under local anesthesia. When not possible or safe to obtain biopsies in the clinic, post-treatment biopsies will not be obtained.