Subjects who are alive at the end of follow up will be censored at the last known date alive. 10.4.4 Safety Analyses Safety endpoints will be analyzed as summary statistics during treatment and/or as change scores from baseline assessments. AEs will be coded as defined in the Medical Dictionary for Regulatory Activities (MedDRA). All AEs will be recorded and tabulated following each treatment. AEs will be recorded by severity, frequency, and relationship to the study intervention and will be presented by System Organ Class (SOC) designations and preferred term groupings. Information on each AE will include start date, stop date, severity, relationship, expectedness, outcome, and duration. Adverse events leading to premature discontinuation from the study intervention and serious treatment -emergent AEs will be presented either in a Table or a Listing. In addition, overall safety will be assessed by descriptive analyses using tabulated frequencies of AEs by grade using CTCAE Version 5 within dose cohorts and for the overall study population in terms of treatment- emergent AEs, SAEs, and clinically signifi cant changes in safety laboratory tests, physical examinations, ECGs, and vital signs. Patients in cohort 2 will have their safety evaluated as detailed in S ection 3.4.3, with up to 12 patients, with further evaluation focusing on bleeding events in the maximum of 12 patients enrolled at the dose considered safe among the patients in this cohort also being enrolled for an exploratory evaluation of efficacy. 10.4.5 Baseline Descriptive Statistics Baseline Characteristics will be described. 10.4.6 Planned Interim Analyses Interim assessment of efficacy will be made according to the Simon two stage phase II designs of each cohort described in S ection 10.4.6. 10.4.7 Tabulation of I ndividual Participant Data Individual responses in a cohort may be depicted within a larger group using a waterfall plot or spider diagram. 10.4.8 Exploratory Analyses 10.4.8.1 Exploratory Analyses: Immune Responses Where feasible exploratory immune analyses will be conducted to evaluate ant i-tumor immune responses . Immune response will be assessed among all subjects treated in each cohort. The magnitude of immune responses will be described. A subject will be considered evaluable for immune response if they receive at least one dose of treatment. 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 Wil coxon rank sum tests as appropriate will be performed on percentages of TNF- α and/or IFN -γ 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 78 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 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 [38]. 10.4.8.2 Exploratory Analyses: Preliminary Activity in Patients Receiving Lower Doses In patients who receive reduced initial doses of therapy as per Section 3.4.3, both in the dose seeking portion as well as in a small group of patients treated at the safe dose, t he percentage of subjects who achieve an objective confirmed complete or partial overall tumor response using RECIST Version 1.1 for a specific initial dose will be evaluated. If anti -tumor responses are observed, the 95% confidence interval of the response rate will be evaluated. 11 COLLABORATIVE AGREEMENTS 11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) A CRADA (02666) is in place with EMD Serono for the supply of M7824 and NHS -IL12. A CRADA ( 03279) is in place with PDS Biotechnology for the supply of PDS0101. 12 HUMAN SUBJECTS PROTECTIONS 12.1 RATIONALE FOR SUBJECT 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, p atients with poorly controlled HIV as well as patents with detectable viral loads of hepatitis B and C will be excluded. Participants 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. . 12.2 P ARTICIPATION OF CHILDREN Individuals under the age of 18 will not be eligible to participate in this study because of unknown toxicities in pediatric patients. 12.3 P ARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT Adults unable to provide consent are excluded from enrolling in the protocol. However, it is possible that subjects enrolled in the protocol may permanently lose the capacity to consent for themselves during the course of this study. In the event this occurs, the subjects will remain in the study because there is a prospect of direct benefit from research participation . All subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision make r 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. 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 . 79 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 Please see Section 12.5.1 for consent procedure. 12.4 RISKS/BENEFIT ASSESSMENT Participants will receive evaluation of their disease at the National Cancer Institute’s Clinical Center. The potential benefit to a participant that goes onto study is a reduction in the bulk of their tumor which may or may not have a favorable impact on symptoms and/or survival. Potential adverse reactions attributable to the administration of the study drug utilized in this trial are discussed in Section 14. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. P articipants will be examined and evaluated prior to enrollment. All evaluations to monitor the treatment of participants will be recorded in the medical record . If participants suffer any physical injury as a result of the participation in this study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland. Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which participants are entitled under applicable regulations. 12.4.1 Risks Some of the procedures performed on this study are not known to be associated with risk. These include urine tests and EKGs. Below are a list of procedures and study interventions that are associated with risk. 12.4.1.1 Study Drug Risks Risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document. Participants may be harmed from being in this study by toxicity due to the drug or combination of drugs given during this study. M7824 is similar to immune check point inhibitors. There are preliminary data to suggest that not all patients benefit from immune check point inhibitors nor M7824. Additionally, there are preliminary data to suggest that an unexpectedly rapid progression of disease occurs in some patients receiving immunotherapy such as immune checkpoint inhibitors. 12.4.1.2 Risk of Optional Biopsies All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure -related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. 12.4.1.3 Risks of Exposure to Ionizing Radiation This research study involves the possibility of 7 CT CAP scans, 1 brain CT scan, and 2 CT guided biopsies collected for research purposes. The amount of radiation exposure you will receive from these procedures is equal to approximately 9.4 rem. The CT scans and CT guided biopsies in this study will expose the research participant to 31.3 years’ worth of background radiation. This level of exposure results in an increased risk of cancer. 80 Abbreviated Title: Combo Immunotx in HPV Cancers Version Date: 05.12.2023 12.4.1.4 Additional Risks of CT S cans In addition to the radiation risks addressed above, CT scans that employ contrast may cause allergic reactions, injection site reactions abdominal discomfort and fainting. 12.4.1.5 Research Blood Collection Risks Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting.