PD-L1 t-haNK, NAI IL-15sa and Cetuximab for Recurrent, Metastatic HNSCC

Inclusion Criteria:

* Participants must have an existing histologically confirmed diagnosis of head and neck squamous cell carcinoma (HNSCC) with evidence of recurrent, metastatic (R/M) or locoregionally advanced, incurable or unresectable disease from any mucosal subsite including oral cavity, oropharynx, larynx, hypopharynx, nasal cavity, and the paranasal sinuses.
* Participants must have at least one RECIST v1.1 measurable lesion, as 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) ≥ 1 cm with CT scans or MR imaging.
* Must have had at least 1, but no more than 2, prior lines of prior systemic therapy for R/M HNSCC; one of these lines should have included anti-PD-1/L1 therapy.

  * a.Platinum-based therapy as part of definitive/adjuvant or curative-intent treatment can count as 1 prior line of therapy if the subject progressed within 6 months of receiving therapy.
  * b. At least 2 weeks must have elapsed since the end of prior chemotherapy, biological agents (2 weeks for anti-cancer monoclonal antibody containing regimens) or any investigational drug product, with adequate recovery of treatment-related toxicity to NCI CTCAE v5 grade ≤1 (or tolerable grade 2) or back to baseline (except for alopecia or peripheral neuropathy).
* Be ≥18 years of age on the day of signing informed consent.
* Must provide prior documentation on tumor PD-L1 expression status and HPV status (for oropharyngeal cancer cases), if available from the medical record.
* Have a performance status of 0 or 1 on the ECOG Performance Scale (see Appendix A).
* Participants must have adequate organ and marrow function as defined below (within 14 days prior to study registration):

  * a. ANC ≥1,000/mcL
  * b. Hemoglobin ≥9 g/dL
  * c. Platelets ≥100,000/mcL
  * d. Total bilirubin ≤ upper limit of normal (ULN)
  * e. AST(SGOT)/ALT(SGPT) ≤2.5x institutional ULN (or ≤1.5x institutional ULN if concomitant with alkaline phosphatase \>2.5x institutional ULN) or ≤5x ULN for those with liver metastases
  * g. Serum creatinine ≤1.5x ULN or creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above 1.5x ULN
* Baseline tumor measurements must be documented from imaging within 28 days prior to study registration.
* Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 7 days of study registration. Female subjects should not become pregnant or nurse a baby during the study and through 120 days after the last dose of study drugs. Male subjects should use a condom as a contraceptive during the study and through 120 days after the last dose of study drugs.

Sperm donation is discouraged for up to 6 months after the last dose of study drug.

-Be willing and able to provide written informed consent for the trial.

Exclusion Criteria

* Have been previously treated with 3 or more lines of systemic therapy for R/M HNSCC.
* Have received radiation therapy (RT) within 10 days of starting protocol therapy.
* Solid organ transplant (allograft) recipients.
* Participant has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging and off systemic steroids for at least 3 weeks prior to study registration) and have no evidence of new or enlarging brain metastases.
* A history of significant autoimmune disease as judged by the treating investigator and on active therapy including prednisone ≥10 mg daily dose equivalent of corticosteroids.
* Uncontrolled intercurrent illness including but not limited to ongoing or active infection; evidence of symptomatic congestive heart failure, unstable angina pectoris, stroke, or ventricular arrhythmia within 6 months of enrollment.
* Has a known additional malignancy that is progressing or requires active treatment. Exceptions might 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.
* Any known positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative). Patients with HIV are eligible if their plasma HIV viral load is undetectable at baseline on antiretroviral therapy.
* Subjects who are pregnant, or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Breastfeeding should be discontinued if the mother is treated on this protocol. Women who could potentially become pregnant while undergoing treatment on this protocol must be willing to use 2 methods of contraception.