Testing Whether Cemiplimab (REGN2810) Plus CDX-1140 Given Prior to Surgery Are Better Than Cemiplimab (REGN2810) Alone in Patients With Stage III-IV Head and Neck Cancer

This study is testing whether giving two immunotherapy drugs — cemiplimab (a PD-1 blocker) and CDX-1140 (a CD40 agonist that activates immune cells) — before surgery can improve outcomes for people with stage III-IV head and neck squamous cell cancer of the mouth, throat, or voice box. **You may be eligible if...** - You have been diagnosed with stage III or IV head and neck squamous cell cancer involving the mouth, throat, larynx, hypopharynx, or nasal cavity - Your tumor is accessible for biopsy - Your cancer is either newly diagnosed or has returned after prior treatment - If your cancer is in the oropharynx (throat), it must be HPV-negative (p16-negative) - You are 18 or older with an ECOG performance status of 2 or below - Your blood counts and organ function are within acceptable ranges - If you have HIV, it must be well controlled on treatment **You may NOT be eligible if...** - You have active autoimmune disease requiring systemic treatment - You are on long-term systemic steroids - You have had prior treatment with PD-1/PD-L1 blockers - You are pregnant or breastfeeding - You have significant heart, lung, or liver conditions Talk to your doctor to see if this trial is right for you.