Phase 2 Study of NAI, HPV Vaccine, and Nab-Paclitaxel in HPV-Positive Oropharyngeal Cancer Followed by De-Intensified Radiation Compared With Standard Chemoradiation

Inclusion Criteria: 1. Age ≥ 18 years old. 2. Able to understand and provide a signed informed consent that fulfills the relevant Institutional Review Board (IRB) or Independent Ethics Committee (IEC) guidelines. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 4. Histologically confirmed squamous cell carcinoma of the oropharynx that is HPV-positive (p16 immunohistochemistry positive and/or HPV DNA positive). Patients with cervical lymph node metastases from an unknown primary can be included if p16-positive and likely OPSCC origin. 5. Locally advanced, stage III/IV HPV-associated OPSCC that is a candidate for definitive chemoradiation. Specifically, tumors classified as T3 or T4 and/or node-positive disease (N2 or N3), without distant metastases (M0). Patients with very low-risk disease (e.g. T1-T2 N0-1) are excluded, as these might be handled with less intensive standard therapy or surgery rather than this trial approach. 6. No prior definitive treatment for the current OPSCC. Patients must be treatment-naïve with respect to chemotherapy, radiation, or investigational therapy for this cancer. Prior diagnostic biopsy is allowed, but no prior curative surgery or radiation to the head and neck. 7. Participants should be suitable for organ-preserving therapy (i.e., radiation) with no immediate need for surgical resection (the trial is non-surgical upfront). 8. Must be willing to accept the randomized treatment assignment after the safety lead-in. During the initial safety phase, all participants receive experimental therapy; once randomization begins, patients and investigators will not choose the arm - it will be assigned by the randomization schedule. Enrolled patients should have no clear contraindication to either arm's therapy (for instance, a patient who absolutely cannot receive cisplatin due to allergy or comorbidity might not be suitable, since cisplatin is required in both arms). The inclusion/exclusion criteria are structured to ensure a homogeneous population suitable for both the experimental approach and SOC chemoradiation. 9. Ability to attend required study visits and return for adequate follow-up, as required by this protocol. 10. Agreement to practice effective contraception for female participants of child-bearing potential and non-sterile males. Per cisplatin prescribing information, female participants of child-bearing potential must agree to use effective contraception for up to 14 months and non-sterile male participants must agree to use a condom for up to 11 months after last dose of cisplatin. Effective contraception includes surgical sterilization (eg, vasectomy, tubal ligation), orals, injectables, 2 forms of barrier methods (eg, condom, diaphragm) used with spermicide, intrauterine devices (IUDs), and hormonal therapy. Exclusion Criteria: 1. HPV-negative or Non-OPSCC: Tumors that are p16-negative or not in the oropharynx are excluded. 2. Any evidence of distant metastases (M1 disease) excludes the patient, since the trial is for curative-intent local/regional therapy. 3. Previous radiation in the head/neck region or prior chemotherapy/immunotherapy for this cancer disqualifies the patient. We require a clean baseline to assess our regimen. 4. Active autoimmune disease or immunosuppression. The experimental arm includes immunotherapy (IL-15 receptor agonist and IBRX-042 vaccine), patients with active serious autoimmune disorders or those requiring immunosuppressive medications (e.g. chronic steroids \>10 mg prednisone daily) are excluded to avoid severe immune-related complications. Well-controlled or mild autoimmune conditions may be considered on a case-by-case basis if risk is low. 5. Inadequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to baseline: 1. Absolute neutrophil count (ANC) \< 1,500 cells/μL without granulocyte colony-stimulating factor support 2. Platelet count \< 100,000/μL without transfusion 3. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) \> 2.5 × ULN, with the following exception: Participants with documented liver metastases: AST and/or ALT \> 5 × ULN 4. Serum bilirubin ≤ 3 × ULN 5. Creatinine clearance ≤ 50 mL/min (calculated using the Cockcroft-Gault formula). 6. Serum albumin \< 3.0 g/dL. 6. Significant cardiovascular disease (such as New York Heart Association cardiac disease class II or greater), myocardial infarction within 3 months prior to baseline, unstable arrhythmias, or unstable angina. 7. Severe infections at the time of enrollment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia. 8. History of human immunodeficiency virus (HIV) with current CD4+ T-cell count \< 350 cells/μL and/or a detectable HIV viral load. 9. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the participant at high risk for treatment complications. 10. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. 11. Participation in an investigational drug study or history of receiving any investigational treatment within 30 days prior to the start of treatment on this study. 12. Assessed by the Investigator to be unable or unwilling to comply with the requirements of the protocol. 13. Pregnant and nursing women.