Head and Neck Squamous Cell Carcinoma (HNSCC) Clinical Trials

• Participants must have histologically or cytologically confirmed new diagnosis of locally advanced, non-metastatic, head and neck squamous cell carcinoma of the oropharynx (cT1-4 N0-N3 M0)

• Participants must be deemed unresectable by a head and neck surgeon for one or more of the following reasons:

‣ Inability to obtain a R0 resection with a minimally invasive surgical approach, such as Transoral Robotic Surgery (TORS)

⁃ Risk of significant functional deficit with a surgical treatment approach

⁃ Other anatomical (such as retropharyngeal location of the carotid artery) or tumor characteristics that in the surgeon's judgment would be a contra-indication to a minimally invasive surgical approach.

• Participants with newly diagnosed HNSCC who underwent partial surgical resection and have gross residual disease are eligible for the study if additional treatment is required.

• Participant must have a tumor that is HPV-16 positive and express p16INK4A. Archival tissue or formalin fixed, paraffin-embedded (FFPE) tissue from a biopsy and/or surgery must be available for HPV-16 and p16INK4A testing on all participants enrolled. All tumors must test positive for HPV-16 using ISH analysis or using HPV16 specific PCR testing and p16INK4A expression in tumor cells using IHC analysis.

• Archival tissue or formalin fixed, paraffin-embedded (FFPE) tissue from a biopsy and/or surgery must be available for PD-L1 staining. Tumors must be scored for CPS.

• Participants must have HLA-A\*0201 genotype as determined by genomic testing.

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) for non-nodal lesions and \> 15mm (\>1.5 cm) for nodal lesions with CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam. See section 11 (Measurement of Effect) for the evaluation of measurable disease.

• Age ≥18 years. Since no dosing or adverse event data are currently available on the use of CUE-101 alone or in combination with pembrolizumab in participants \<18 years of age, children are excluded from this study.

• ECOG performance status of 0 or 1 (Karnofsky ≥60%, see Appendix A).

• Participants must have adequate organ and marrow function as defined below in the protocol

• Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.

• A male participant must agree to use of a highly effective method of contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.

• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

‣ Not a woman of childbearing potential (WOCBP) as defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal or

⁃ A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.

⁃ Highly effective methods of contraception:

• i. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal.

∙ ii. Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable.

∙ iii. Non-hormonal (copper) intrauterine device. iv. Intrauterine hormone-releasing system. v. Bilateral tubal occlusion/ligation. vi. Sexual abstinence, i.e., refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant).

∙ vii. Vasectomized sexual partner (provided that partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has received medical assessment of the surgical success).

• Ability to understand and the willingness to sign a written informed consent document.