Background: HPV+ OPC is associated with excellent survival, yet standard therapy leads to substantial treatment-related toxicity. Among various de-escalation strategies, response adaptive de-escalation which selects pts based on neoadjuvant response is promising with excellent survival and reduced toxicity. Strategies to further deepen responses may allow more pts to be de-intensified which may improve survival and further reduce toxicity. As generation and maintenance of the HPV16+ malignant state of a cell requires the consistent expression of HPV-specific E7 and E6 oncoproteins, they represent a potential immunotherapy target, inspiring the development of HPV-specific immune activators, such as HB-200 platform. This platform contains two replicating live-attenuated vectors based on either lymphocytic choriomeningitis virus (HB-201) or Pichinde virus (HB-202), which express the same non-oncogenic (but highly antigenic) HPV16 E7E6 fusion protein and infect antigen presenting cells to induce and activate tumor-specific T cell responses. Data from in vivo models and early phase clinical studies indicate that HB-201 monotherapy and HB-201/HB-202 alternating two-vector therapy induces a robust antigen-specific circulating T cell response and anti-tumor activity, suggesting potential to provide therapeutic benefit to pts with HPV16+ OPC. Based on these studies we hypothesized that incorporation of the HB-200 platform with neoadjuvant chemotherapy followed by risk/response-stratified de-escalation in our ongoing randomized phase I/II study may deepen responses and facilitate de-escalation in a greater proportion of pts (NCT05108870). Methods: Eligible pts must have previously untreated HPV16+ OPC with T3-4 or N2-3 (AJCC-7^th edition). Very low-risk disease with T1-2 and N0-1 are excluded. Pts receive neoadjuvant therapy with either HB-201 or HB-201/HB-202 alternating two-vector therapy for 3 doses in combination with carboplatin AUC 5 day 1 and paclitaxel 100mg/m2 on days 1/8/15 of 21-day cycle for three cycles followed by risk/response adapted locoregional therapy with transoral robotic surgery (TORS) or RT to 50Gy (single-modality), CRT to 50Gy with cisplatin (intermediate de-escalation), or CRT to 70Gy with cisplatin (regular dose CRT). Eight pts have been enrolled in phase I portion with planned 74 pts (37 pts per arm) in phase II. The primary endpoint is deep response rate defined as proportion of patients with ≥50 shrinkage per RECIST v1.1. Secondary endpoints include OS, PFS, locoregional and distant control, and safety/tolerability. Exploratory analyses will include cell free HPV-DNA, and tissue/blood-based assessment of specific anti-tumor immunity. Clinical trial information: NCT05108870.