NT-I7 for the Treatment of Recurrent Squamous Cell Carcinoma of Head and Neck Undergoing Surgery

Inclusion Criteria:

* Patients must have histologically or cytologically confirmed squamous cell carcinoma of oral cavity, oropharynx, hypopharynx or larynx with recurrent disease which is amenable for curative intent surgical resection
* Age \>= 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* Absolute neutrophil count \>= 1,500/microliter (mcL)
* Platelets \>= 100,000/mcL
* Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) unless elevated due to Gilbert's syndrome and direct bilirubin is within normal limits
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) =\< 3 X institutional upper limit of normal
* Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT) =\< 3 X institutional upper limit of normal
* Alkaline phosphatase =\< 2.5 x ULN (=\< 5 x ULN for subjects with documented liver involvement or bone metastases)
* Creatinine =\< 1.5 x within institutional upper limit of normal OR
* Creatinine clearance glomerular filtration rate (GFR) \>= 50 mL/min/1.73 m\^2,calculated using the Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m\^2
* Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Individuals 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
* The effects of NT-I7 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception for the duration of study participation and for 3 months after the study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation for 3 months after the study treatment

Exclusion Criteria:

* Had received immune check point inhibitor within 6 weeks prior to study entry OR chemotherapy, radiation therapy or surgery within 4 weeks prior to study entry except palliative radiotherapy to non-target lesions (within 2 weeks prior to study entry)
* Has history of autoimmune disease which requires active immune suppression (steroid replacement for iatrogenic deficiencies, prednisone 5 mg or less \[or equivalent dose\], or topical steroids are allowed)
* Is currently receiving any other investigational agents
* Has uncontrolled tumor-related pain
* Has uncontrolled intercurrent medical illness, including but not limited to congestive heart failure, recent acute cardiac event within 6 months, and recent major bleeding event within 6 months
* Pregnant women are excluded from this study because effects of NT-I7 on developing fetus is unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with NT-I7, breastfeeding should be discontinued if the mother is treated with NT-I7
* Is not recovered from adverse events (AEs) (other than alopecia, vitiligo, neuropathy or endocrinopathy managed with replacement therapy) due to agents administered more than 4 weeks earlier (i.e., have residual toxicities \> grade 1)
* Had major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to study initiation
* Had concurrent or previous other malignancy within 5 years of study entry, except noninvasive or indolent malignancy
* Has spinal cord compression not definitively treated with surgery and/or radiation
* Has active autoimmune diseases including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis
* Has active and clinically relevant bacterial, fungal, viral, or Tuberculosis (TB) infection, including known Hepatitis A, B, or C or human immunodeficiency virus (HIV) (testing not required) or have been hospitalized within 4 weeks prior to NT-I7 injection