Supplier Precigen, Inc. EMD Serono, Inc. Commercial Agents: None 2 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 PRÉCIS Background Metastatic HPV associated malignancies (cervical, anal, oropharyngeal cancers, etc.) are often incurable and poorly palliated by standard therapies. HPV-positive (p16+) oropharyngeal cancers are the most common HPV-associated malignancy in the United States and are increasing in incidence. Stage II and III HPV-positive oropharyngeal cancer is primarily treated with definitive therapy. Although the prognosis for stage I HPV+ oropharyngeal cancer is favorable, about 20 percent of patients with stage II disease and 35 percent of patients with stage III disease will die within four years. Attempts to de-intensify treatment of HPV-positive oropharyngeal cancer by replacing high-dose cisplatin with cetuximab concurrent with radiotherapy have failed. Induction and neoadjuvant immunotherapy are an area of active study in this type of cancer. The aims of induction immunotherapy are to induce antigen-specific immunity prior to definitive therapy and to reduce the risk of disease relapse for patients with stage II and III disease. Therapeutic vaccines targeting HPV alone or in combination with M7824 (dual PD-L1 and TGF beta inhibitor) have demonstrated induction of HPV antigen-specific responses and tumor growth inhibition in multiple pre-clinical models of HPV-positive malignancy. In clinical studies done in the CCR, M7824 as monotherapy has produced a notable objective response rate (35-40%) for metastatic HPV + cancers including Oropharyngeal Squamous Cell Carcinoma (OPSCC) and preclinical studies support the addition of an investigational HPV vaccine with therapeutic intent (PRGN-2009, a gorilla adenoviral based vaccine) to further increase anti-tumor efficacy. Objectives: Phase I in participants with recurrent/metastatic HPV positive cancer: Primary objective: To determine the safety and recommended phase II dose (RP2D) of PRGN-2009 (HPV vaccine) alone or in combination with M7824 administered at RP2D of 1200 mg q2w. Phase II in participants with newly diagnosed stage I (T1,T2 N1)/II/III p16-positive oropharyngeal cancer and patients with newly diagnosed operable stage II/III/IVA/IVB HPV+ sinonasal squamous cell cancer: Primary objective: To determine if HPV vaccine alone (Arm 2A) is able to result in a  2- fold increase in CD3+ tumor infiltrating T cells post treatment compared with pre- treatment in p16-positive oropharyngeal cancer. Eligibility: Phase I: Men or women of age > 18 years old. 3 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 Subjects with cytologically or histologically confirmed locally advanced not amenable to potentially curative local therapies or metastatic HPV associated malignancies: oCervical cancers; op16+ Oropharyngeal cancers; oAnal cancers; oVulvar, vaginal, penile, and squamous cell rectal cancers oOther locally advanced or metastatic solid tumors (e.g., lung, esophagus) that are known HPV+. Prior first line systemic therapy is required. Phase II: Men or women of age > 18 years old. Subjects with newly diagnosed stage I (T1,T2 N1), II or III p16-positive oropharyngeal squamous cell carcinoma (OPSCC) or stage II/III/IVA/IVB HPV-SNSCC planned for definitive therapy. Design: Phase I: Recurrent/metastatic HPV associated cancer: A 3+3 dose escalation design will be used which will evaluate PRGN-2009 (HPV vaccine) at two dose levels (1x1011 and 5x1011 viral particle (VP) units) given as monotherapy followed by a third dose level evaluating the RP2D dose of PRGN-2009 in combination with 1200 mg (RP2D) of M7824. In addition, the combination of PRGN-2009 at RP2D with 1200 mg of M7824 will be expanded to a total of 10 evaluable participants to gauge the preliminary efficacy of the combination of PRGN-2009 and M7824 in participants with advanced disease. There will be a 4-week DLT evaluation period for each dose level.