The percentage of subjects with a positive immune response will be evaluated by cohort. For flow cytometry analyses on PBMC samples, Student T tests or Kruskal-Wallis and Wilcoxon rank sum tests as appropriate will be performed on percentages of TNF- and/or IFN- expressing cells among the different cohorts to determine any significant differences in cell populations. For antigen specific T cell responses, a positive immune response is defined by CMI reactivity in ex vivo stimulation using a flow cytometric readout (cytokine production or CD107 expression). Antigen-specific peptide challenge assays require a readout of >250 reactive T-cells/million cells above the background (53). 11 COLLABORATIVE AGREEMENTS 11.1 COOPERATIVE R ESEARCH AND DEVELOPMENT AGREEMENT (CRADA) A CRADA (02666) is in place with EMD Serono for the supply of M7824. A CRADA (03209) is in place with Precigen for the supply of PRGN-2009. 12 HUMAN SUBJECTS PROTECTIONS 12.1 RATIONALE F OR S UBJECT SELECTION Subjects from all racial/ethnic groups are eligible for this study if they meet the eligibility criteria. Efforts will be made to extend accrual to a representative population. Due to impaired cellular immunity which may affect the efficacy of treatment, participants with poorly controlled HIV as well as patents with detectable viral loads of hepatitis B and C will be excluded. Patients who do not accept blood transfusions will be excluded. As there is a risk of severe bleeding with this study drug, participants must be willing to receive blood transfusions if medically necessary for their own safety. Participants must be able to receive blood transfusions in order to minimize the risks of receiving M7824. In addition, these patients could compromise the scientific validity of the study. For example, death from blood loss could make it difficult to assess other aspects of the investigational immunotherapy’s safety—a primary scientific goal in this early-phase immunotherapy trial, which are carried out in small numbers of participants. 12.2 PARTICIPATION OF C HILDREN Individuals under the age of 18 will not be eligible to participate in this study because of unknown toxicities in pediatric patients. 12.3 PARTICIPATION OF S UBJECTS UNABLE TO GIVE C ONSENT Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (Section 12.4.2), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the “NIH Advance Directive for Health Care and Medical Research Participation” form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. 75 Abbreviated Title: Combo Immunotx in HPV OPSCC Version Date: 04.25.2023 Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR as needed. Please see Section 12.5.1 for consent procedure.