Background: Concurrent therapy for PULA HNSCC using the EGFR-specific mAb cetuximab (C) plus IMRT is an accepted standard, however disease control in intermediate or high risk disease could be improved. Our recent data indicate that C induces Ab-dependent, cell-mediated cytotoxicity and cross-priming of cytotoxic T lymphocytes. However, C also induces immunosuppressive regulatory T cells (Treg) expressing the checkpoint receptor CTLA-4; Treg correlate negatively with clinical outcomes to C. We hypothesize enhanced C-induced antitumor cellular immunity and clinical activity by targeting Treg with the anti-CTLA-4 mAb ipilimumab (ipi). We are conducting a phase I study adding ipi to C-IMRT in patients (pts) with intermediate or high risk PULA HNSCC. Methods: Eligible pts have stage III-IVb PULA HNSCC (pharynx, larynx). “High risk” pts are HPV(-). “Intermediate risk” pts are HPV(+) and have either: 1) ≥ 10 pack-year tobacco and ≥N2 disease; or 2) T4 or N3 disease, irrespective of tobacco status. A phase I (3+3) dose escalation trial is evaluating the addition of ipi to standard concurrent C (250 mg/m²weekly after loading dose) + IMRT (66-70 Gy daily fractionation over 7 weeks). See table for dose cohorts and schedule. Dose limiting toxicity (DLT) is defined as any grade 4 toxicity (except in-field radiation dermatitis or asymptomatic, correctable lab abnormality), or any toxicity which delays IMRT ≥ 10 fractions. The DLT observation period ends 4 weeks after completing IMRT. As of Jan 2014, 3 pts have enrolled in the first cohort, receiving ipi at 3mg/kg. The next dose tier, assuming no DLTs, will increase ipi to 10 mg/kg. In the event of DLT at 10 mg/kg, ipi dosing will de-escalate to 6 mg/kg. Extensive immune monitoring is underway using baseline tumor tissue, including characterization of tumor-infiltrating lymphocytes, and serial monitoring of circulating lymphocytes and cytokines. Clinical trial information: NCT01935921.