Doctors leading this study will give blood tests to head and neck cancer participants during the beginning of chemotherapy treatment (also known as induction therapy) to see if these blood tests can help predict tumor shrinkage after therapy and reduce the amount of additional radiotherapy or chemotherapy treatment the participant may need. This study will also examine ways to reduce overall side effects of treatment using robotic surgery, chemotherapy and radiotherapy, or radiotherapy alone.

Inclusion Criteria:

1. Subjects must have clinically confirmed Human papillomavirus(HPV)-positive head and neck squamous cell cancer of the back of the mouth/throat (oropharynx). Confirmed HPV-positive disease of other subsites are uncommon but also eligible.

2. HPV testing must be compliant with the following criteria:

   1. P16INK4a immunohistochemistry (p16 IHC) positivity is sufficient to enroll and initiate treatment (p16 IHC interpretation to follow guidelines by Jordan and Lingen et al72).
   2. p16 IHC positivity is to be validated using an HPV Polymerase chain reaction (PCR - a type of DNA copying method).
   3. HPV PCR must demonstrate HPV16 or HPV18 subtype

3. Availability of greater than 10 unstained 5 micron slides (to be provided to HTRC at the University of Chicago). Patients who cannot fulfill this requirement will need to undergo a new biopsy prior to enrollment on study.

4. Participants must be at least 18 years old.

5. Participants with American Joint Committee on Cancer (AJCC) (8th edition, 2018) N1 (>=3cm), N2-N3 nodal disease or T3-T4 primary tumor.

6. Measurable disease (either primary site or nodal disease) according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria.

7. No previous radiation or chemotherapy for a head and neck cancer.

8. No complete surgical resection for a head and neck cancer within 8 weeks of enrollment (although lymph node biopsy including excision of an individual node with presence of residual nodal disease, or surgical biopsy/excision of the tumor with residual measurable disease is acceptable.) No surgical procedures or biopsies will occur after baseline scans are performed and measurable lesions are identified.

9. Eastern Cooperate Oncology Group performance status 0-1

10. Normal organ function clinically confirmed by medical records.

11. Participants must sign a study-specific informed consent form prior to study entry. Participants should have the ability to understand and the willingness to sign a written informed consent document.

12. Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug.

13. Women must not be breastfeeding.

14. Women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment.

15. Men who are sexually active with women of childbearing potential must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s).

Exclusion Criteria:

1. Any sign of metastatic disease (M1 disease).
2. Non-HPV16/18 subtype
3. Unidentifiable primary site of cancer.
4. Other medical illnesses that may impair the participant's ability to receive therapy or limit survival. This includes but is not limited to ongoing or active infection, immunodeficiency, symptomatic congestive heart failure, pulmonary dysfunction, cardiomyopathy, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance. Patients with clinically stable and/or chronically managed medical illnesses that are not symptomatic and/or are not expected to impact treatment on protocol are still eligible (conditions to be reviewed by the PI to confirm eligibility)
5. Prior surgical therapy other than incisional/excisional biopsy or organ-sparing procedures such as debulking of airway-compromising tumors. Residual measurable tumor is required for enrollment as discussed above.
6. Patients receiving other investigational agents.
7. Prior systemic anti-cancer treatment within the last 8 weeks.
8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or any tumors that are not likely to influence life expectancy in the subsequent 3 years without active treatment.
9. Has known history of, or any evidence of active, non-infectious pneumonitis.
10. Has a history of HIV.
11. Has known active Hepatitis B or hepatitis C. If eradicated, patient is eligible.
12. Has received a live vaccine within 28 days of planned start of study therapy.