Pembrolizumab + N-803 Alone or in Combination With PD-L1 t-haNK Cells for Resectable Head and Neck Squamous Cell Carcinoma

Background:

• Even in the potentially curative setting, human papillomavirus (HPV)-unrelated head and neck squamous cell carcinomas (HNSCC) are associated with dismal outcomes (compared to HPV-related) despite maximal surgical and adjuvant treatment (i.e., radiotherapy +/-chemotherapy).
• The window period between diagnosis and curative surgery provides a window of opportunity to administer therapies that may improve outcomes.
• Four published clinical trials suggest that neoadjuvant checkpoint blockade can improve recurrence-free survival (RFS) in resectable HNSCC (NCT02919683, NCT02488759, NCT02296684, NCT04247282). This includes NCI protocol 20C0024 (NCT04247282) where in addition to demonstrating improved 1-year RFS compared to historical values, our correlative studies provided insight into potential mechanisms of this benefit.
• N-803 (an IL-15 agonist) combined with anti-programmed cell death protein 1 (PD-1) therapies work toward maximization of T cell-mediated anti-tumor activity, a key component of anti-tumor immunity. However, expression of T cell inhibitory receptors and/or loss of antigen presentation and processing machinery, often driven by T cell activity s release of interferon-gamma renders some tumor cells invulnerable to T cell killing.
• Studies conducted by collaborators at the NCI have shown that programmed death-ligand (PD-L1) t-haNK can lyse such T-cell-resistant tumor cells. Additionally, in a murine model of oral cancer, the triplet of PD-L1 t-haNK combined with pembrolizumab and N-803 resulted in more tumor control than the doublet combinations of these agents.
• PD-L1 t-haNK cells is an allogenic, irradiated (no engraftment), off-the-shelf cell line currently being studied in combination with pembrolizumab and N-803 in advanced/metastatic HNSCC (NCI CCR protocol 000096, (NCT04847466)). As of November 2022, 10 participants have been treated and the regimen has been well tolerated.
• In addition to potentially improving outcomes, testing this triplet in the neoadjuvant setting with pre-and post-treatment tumor biopsies provides an opportunity to gain insight into the mechanisms of this regimen s anti-tumor activity.

Objective:

-To determine the pathologic tumor response (pTR) rate (viable tumor in 50% or less of the surgically resected primary tumor bed) in Arm 1 and Arm 2

Eligibility:

• Histologically or cytologically confirmed previously untreated intermediate/high risk, p16-negative (if oropharyngeal primary tumor), squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV.
• Age >= 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status <= 1 and adequate organ function.

Design:

• This is an open-label, single-site, non-randomized, phase II study to evaluate the efficacy of combined treatment of PD-L1 t-haNK cells, pembrolizumab, and N-803.
• The first 15 participants will be enrolled in Arm 1 and treated with pembrolizumab and N-803, the following participants will be enrolled in Arm 2 and treated with pembrolizumab, N-803, and PD-L1 t-haNK cells.
• All participants (Arm 1 and Arm 2) will receive treatment consisting of one intravenous (IV) infusion of pembrolizumab and one subcutaneous (SC) injection of N-803 on Day 1.
• Participants in Arm 2 will receive additional treatment with IV infusion of PD-L1 t-haNK cells on Days 1, 5, 8, 12, and 15.
• Participants will be monitored for 2 years.

• INCLUSION CRITERIA:
• Histologically or cytologically confirmed previously untreated intermediate/high risk, p16-negative (if oropharyngeal primary tumor), squamous cell carcinoma of the head and neck (T1-T4, N0-N3, M0 stage II, III or IV). Note: p16 status will be determined by a history of p16 immunohistochemistry (IHC) staining conducted per standard of care.
• Age >= 18 years.
• ECOG performance status <= 1.
• Planned for cancer removal surgery per standard of care.
• Participants must have adequate organ and marrow function as defined below:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 3.0 x upper limit of normal (ULN)
• Total bilirubin <= 1 x ULN. Note: Participants with Gilbert's syndrome can have total bilirubin < 3.0 mg/dL
• Absolute neutrophil count (ANC) >= 1.0 x 10^9/L
• Hemoglobin (Hgb) >= 10.0 g/dL
• Platelet count >= 100 x 10^9/L
• Prothrombin time (PT) and partial thromboplastin time (PTT) <= 1 x ULN. Note: Participants with prolonged PTT determined to be due to lupus anticoagulant are eligible
• Creatinine <= 1.5 x ULN
• Participants with a history of human immunodeficiency virus (HIV) infection must:

• be on effective anti-retroviral therapy; and
• have the viral load < 400 copies/mL; and
• have the CD4 count > 150 cells/microL
• Participants with a history of Hepatitis C virus (HCV) infection must

• received curative treatment; and
• have an undetectable viral load.
• Individuals of child-bearing potential (IOCBP) and those who can father children must agree to use an effective method of contraception (barrier, hormonal, intrauterine device (IUD), surgical sterilization) for the duration of the study treatment and up to 4 months after the last dose of the study drug (s).
• Nursing participants must be willing to discontinue nursing from study treatment initiation through 4 months after the last dose of the study drug(s).
• Participants must have a primary tumor site that is amenable to biopsy and be willing to undergo pre-and post-treatment biopsies.
• The ability of a participant to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• History of allergic reactions attributed to compounds of similar chemical or biological composition to drugs used in the study.
• Active immunosuppressive treatment equivalent of > 10mg of prednisone daily. Note: Short-course systemic corticosteroids (e.g., prevention/treatment for transfusion reaction) or use for a non-cancer indication (e.g., adrenal replacement) is acceptable.
• History of autoimmune disease with the exception of controlled thyroid disease, psoriasis not requiring medications, vitiligo, and alopecia.
• Participants with a history of hepatitis B (HBV).
• Prior malignancy active within the previous 2 years except for locally curable cancer that is currently considered cured and does not require an additional standard of care treatment, such as cutaneous basal or squamous cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an incidental histological finding of prostate cancer.
• Prior therapy with the investigational drug within 2 weeks prior to the treatment initiation.
• Pregnancy (confirmed with Beta-human chorionic gonadotropin (Beta-HCG) serum or urine pregnancy test performed in individuals of childbearing potential at screening).
• Uncontrolled intercurrent illness or medical condition(s) evaluated by medical history and physical exam or situations that are not stable (e.g., recent hospitalization, Emergency Room visit or undergoing medication changes) that the investigator assesses would unacceptably increase of participation in the trial for the participant or impair the ability to evaluate the endpoints of the study.