Background:
- Natural killer (NK) cells are an important component of an anti-tumor immune
response.
- PD-L1 CAR-NK (PD-L1 t-haNKs) is an off the shelf, irradiated human, allogeneic, NK
cell line that is frozen, shipped, thawed and then infused.
- PD-L1 CAR-NK cells have been engineered to have 3 adaptive modifications:
- Expression of a chimeric antigen receptor (CAR) targeting the tumor-associated
antigen PD-L1
- Expression of the high-affinity variant (158V) of the human Fcy receptor
(FcyRIIIa/CD16a)
- An endoplasmic reticulum-retained version of the human interleukin-2 (ERIL-2)
cytokine.
- To improve the safety profile, PD-L1 CAR-NK cells are irradiated, thus inhibiting
proliferation while maintaining cytotoxicity.
- Irradiated PD-L1 CAR-NK cells are highly effective at lysing PD-L1 expressing tumor
cells as well as PD-L1 null tumor cells (via expression of native NK cell
receptors).
- Preliminary clinical data from 10 participants treated with PD-L1 CAR-NK cells
(NCT04050709) suggest PD-L1 CAR-NK are well tolerated at a dose of 2x10^9 cells
intravenous (IV) twice per week. An additional 8 participants have received
irradiated PDL1 CAR-NK under single patient INDs. PD-L1 CAR-NK cell treatment
combined with PD-1 blockade and cytokine therapy may synergistically activate the
T-cell and NK cell arms of the immune system and enhance anti-tumor activity.
- The combination of N-803 + PD-1/PD-L1 interaction blockade has a manageable safety
profile
Objectives:
- Determine the 6-month progression free survival with irradiated PD-L1 CAR-NK cells
in combination with N-803 plus pembrolizumab in participants with gastric/GEJ
cancer.
- Determine the clinical response rate (CR+PR) with irradiated PD-L1 CAR-NK cells in
combination with N-803 plus pembrolizumab in participants with Head and neck
squamous cell carcinoma.
Eligibility:
- Gastric/GEJ cancer Cohort
- Participants must have metastatic or unresectable locally advanced Gastric/GEJ
cancer.
- Participants must have evaluable disease with or without measurable disease by
RECISTv1.1.
- Participants must have completed, had disease progression on, or been
ineligible to receive first-line systemic chemotherapy for advanced/metastatic
disease and anti-PD-1 therapy for advanced/metastatic disease.
- Participants with HER2 positive disease must have received HER2-targeted
systemic therapy.
- Head and neck squamous cell carcinoma Cohort
- Participants must have metastatic or unresectable locally advanced HNSCC.
- Participants must have measurable disease by RECISTv1.1. If the participant is
one of the first six participants enrolled on study and is part of the
safety-lead in, either measurable or evaluable (e.g., ascites, elevated tumor
marker, or lesion visualized on imaging) disease will be permitted.
- Participants must have received or been ineligible to receive first-line
systemic chemotherapy and must have received systemic anti-PD-1 therapy (in the
first-line or subsequent-line setting).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
- Age >= 18 years
Design:
- This is an open label, single center, phase II trial using a safety lead-in to
assess the safety and tolerability of irradiated PD-L1 CAR-NK cells in combination
with N-803 plus pembrolizumab in participants with head and neck squamous cell
carcinoma and/or gastric/GEJ cancer.
- The phase II objectives of this study is to assess 6-month progression free survival
(PFS) and clinical response rate (CR+PR) in participants with gastric/GEJ cancer and
head and neck squamous cell carcinoma, respectively.
- Participants will enroll and receive 1 dose of PD-L1 CAR-NK cell monotherapy (week
-1) for PK/PD studies before starting the combined treatment of Pembrolizumab and
N-803 one week later (week 0). PD-L1 CAR-NK cells (2x10^9) will be given
intravenously every week until week 6 and then every two weeks from 6 week onward.
- The accrual is 50 evaluable participants. To allow for a small number of inevaluable
participants, the accrual ceiling will be set at 55 participants.