Neoadjuvant Pembrolizumab and IO102-103 for Squamous Cell Carcinoma of the Head and Neck (SCCHN).

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial.

• Be 18 years of age on day of signing informed consent.

• Patients with non-bulky/non-bulky squamous cell carcinomas of the head and neck,with an indication for surgical therapy.

1. Surgically resectable disease - generally that is T1N1-N2B, T2-4N0-N2b stageare generally eligible (AJCC 7th), however exceptions can be made afterapproval by the PI for surgically appropriate cases.

2. If determined per tumor board that a low-volume/non-bulky tumor of anotherstage is appropriate for resection (e.g. small volume T4 with a small amount ofbone invasion) such tumors may also be considered for this study ifrecommendation in tumor board is such.

• Be appropriate candidates for resection and curative intent therapy in general.

• Have a performance status of 0 or 1 on the ECOG Performance Scale.

• Consent to undergo biopsy from a newly obtained core or excisional biopsy of a tumorlesion before study drug administration, and during treatment. Biopsy in case ofprogressive disease is optional.

• Demonstrate adequate organ function

• Female subject of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

• Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile or abstain from heterosexual activity for thecourse of the study through 120 days after the last dose of study medication.Subjects of childbearing potential are those who have not been surgically sterilizedor have not been free from menses for > 1 year.

• Male subjects should agree to use an adequate method of contraception starting withthe first dose of study therapy through 120 days after the last dose of studytherapy.

1. Abstinence is considered an adequate contraception method.

Exclusion Criteria:

• A Women of child bearing potential (WOCBP) who has a positive urine pregnancy testwithin 72 hours prior to treatment allocation/registration . If the urine test ispositive or cannot be confirmed as negative, a serum pregnancy test will berequired.

• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent orwith an agent directed to another stimulatory or co-inhibitory T-cell receptor

• Has received prior systemic anti-cancer therapy for HNSCC including investigationalagents within 4 weeks of first dose of study treatment.

• Has received prior radiotherapy within 2 weeks of start of study intervention.Participants must have recovered from all radiation-related toxicities, not requirecorticosteroids, and not have had radiation pneumonitis. A 1-week washout ispermitted for palliative radiation (≤2 weeks of radiotherapy) to non- Centralnervous system (CNS) disease.

• Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of study drug (including live COVID-19 vaccines). Administration ofkilled vaccines is allowed. Administration of messenger RNA (mRNA) or peptidevaccines (e.g., for COVID-19) is allowed.

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first doseof study intervention.

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of study drug.

• Has a known additional malignancy that is progressing or has required activetreatment within the past 2 years. Participants with basal cell carcinoma of theskin, squamous cell carcinoma of the skin, low grade cancers that are not expectedto impact life expectancy within the next 3 years and not impact interpretation ofthis study are allowed

• Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e., without evidence of progression for at least 4 weeks by repeat imaging

• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs), unless it is systemic steroid therapy equal or less thanoutlined in exclusion criteria 7.

Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement .

therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.

• Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

• Has an active infection requiring systemic therapy.

• Has a known history of Human Immunodeficiency Virus (HIV) infection.

• Has a known history of Hepatitis B or Hepatitis C virus

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with theparticipant's participation for the full duration of the study, or is not in thebest interest of the participant to participate, in the opinion of the treatinginvestigator.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial as per assessment of the treatingphysician. Chronic managed disorders that are not clinically active are acceptable.

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of trial treatment.

• Has had an allogenic tissue/solid organ transplant.

• Congestive heart failure , unstable angina, serious uncontrolled cardiac arrhythmia,a myocardial infarction within 6 months prior to study entry or a history ofmyocarditis