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.