Single-Center Eval of Clinical & Radiological Benefit AHCC in Combo W/ SOC Tx for HPV+ Pts W/ HNSCC

Inclusion Criteria:

• Between 18 and 79 years of age.

• Has a diagnosis of pathologically or cytologically proven HPV positive HNSCC.

• For patients who have undergone surgery, they must be registered at least 4 weeksafter surgery.

• For patients that have completed surgery, has a high risk disease defined as:

1. Positive Margins and/or Extra Nodal Extension (ENE)

2. Positive margins are defined as malignancy at or within 1 mm of the margin.High grade dysplasia (i.e., carcinoma in situ) at the margin is also consideredpositive

3. ENE may be either gross or microscopic

• No evidence of distant disease based on baseline imaging done within 28 days priorto registration. Patient may be any T or N stage, but must be M0

• Has an ECOG Performance Status 0-1.

• Has the ability to understand and the willingness to sign a written informed consentdocument. Patients with impaired decision-making capacity (IDMC) who have a legallyauthorized representative (LAR) or caregiver and/or family member available willalso be considered eligible.

• All females of childbearing potential must have a blood test or urine study within 14 days prior to registration negative for pregnancy.

1. A female of childbearing potential is defined as any woman, regardless ofsexual orientation or whether they have undergone tubal ligation, who meets anyof the following criteria: has achieved menarche at some point, has notundergone a hysterectomy or bilateral oophorectomy, or has not been naturallypostmenopausal (amenorrhea following cancer therapy does not rule outchildbearing potential) for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months).

• Women of childbearing potential and sexually active males must not conceive orfather children by using accepted and effective method(s) of contraception or byabstaining from sexual intercourse while on study treatment, and continue for 120days after the last dose of study treatment. Accepted and effective methods aredescribed in Appendix 4

• Has adequate organ and marrow function as defined below, based on clinicallaboratory assessments obtained ≤ 28 days prior to registration:

1. Absolute neutrophil count (ANC) ≥ 1,500/μL

2. Platelets ≥ 100,000/μL

3. Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)

4. AST or /ALT ≤ 3.0 × institutional ULN

5. Creatinine clearance > 30 mL/min using the Cockcroft-Gault formula

Exclusion Criteria:

• Patient must not be pregnant or breast-feeding due to the unknown potential harm toan unborn fetus and possible risk for adverse events in nursing infants with thetreatment regimens being used.

• Current active infection that requires systemic treatment at time of registration.

• History of solid organ transplant or stem cell transplant.

• Currently taking immunosuppressive medication within 7 days prior to registration,EXCEPT for the following:

1. intranasal, inhaled, topical steroids, or local steroid injection (e.g.,intra-articular injection)

2. systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone orequivalent

3. steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication).

• New York Heart Association Class III or IV heart failure. Patients with knownhistory or current symptoms of cardiac disease, or history of treatment withcardiotoxic agents, should have a clinical risk assessment of cardiac function usingthe New York Heart Association Functional Classification.

• Received a live vaccine within 30 days prior to the first dose of study drug.

1. Examples of live vaccines include, but are not limited to, the following:measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,Bacillus Calmette-Guérin (BCG), or typhoid fever.

2. Seasonal influenza vaccines for injection are generally killed virus vaccinesand are allowed; however, intranasal influenza vaccines (e.g., FluMist®) arelive attenuated vaccines and are not allowed.

3. COVID-19 (SARS-CoV-2) vaccines (mRNA or other) are allowed.

• Known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis Cvirus (defined as positive for HCV RNA on a qualitative test).

• History of HIV with or without antiviral treatment having

1. detectable viral loads within 6 months, or

2. history of Kaposi sarcoma and/or Multicentric Castleman Disease.

• Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency) is not considered a formof systemic treatment and is allowed.

• Known allergy to mushrooms, mushroom products, or any components of the studyformulation.

• Known psychiatric or substance abuse disorder that would interfere with theparticipant's ability to complete study assessments or to adhere to protocolrequirements.