Cancer Res Treat.  2022 Oct;54(4):1005-1016. 10.4143/crt.2021.986.

A Phase I/IIa Randomized Trial Evaluating the Safety and Efficacy of SNK01 Plus Pembrolizumab in Patients with Stage IV Non-Small Cell Lung Cancer

Affiliations
  • 1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 2Division of Hematology/Oncology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
  • 3Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 4Data Convergence Drug Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Korea
  • 5Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 6Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 7NKMAX Co., Ltd., Seongnam, Korea
  • 8Department of Pulmonology and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Abstract

Purpose
The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial.
Materials and Methods
Overall, 18 patients with advanced non–small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/– 6 weekly infusions of SNK01 at either 2×109 or 4×109 cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life.
Results
Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4×109 cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001).
Conclusion
Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events.

Keyword

Non-small cell lung carcinoma; NK cell; Pembrolizumab; Combination therapy

Figure

  • Fig. 1 Clinical trial profile. In total, 20 patients were enrolled to the trial. Except for the first three and the last three patients (cohort 1), the remaining patients were randomly assigned to cohort 0 or 2. The pembrolizumab monotherapy group (cohort 0) received regular therapy with intravenous injection of pembrolizumab (200 mg) on the indicated time. The pembrolizumab plus SNK01 group (cohort 1 or 2) received pembrolizumab plus a total of 6 SNK01 infusions in 42 days, i.e., weekly infusion for 6 weeks. DLT, dose-limiting toxicity; MTD, maximum tolerated dose; NK, natural killer.

  • Fig. 2 Characteristics of expanded NK cells. (A) The percentages of CD3−CD56+ NK cells, CD3+ T cells, CD20+ B cells, and CD14+ monocytes were analyzed flow cytometrically on freshly isolated positive cells using CliniMACS CD56 microbeads (D0; before expansion) and expanded NK cells for 17–18 days of culture (D17–18). (B) The fold expansion of the total cell population after 17–18 days of culture (D17–18). The expression levels of activating receptors, inhibitory receptors, chemokine receptors, perforin, and granzyme B were analyzed flow cytometrically among CD56+ gated cells after 17–18 days of culture. (C) The cytotoxic activity of expanded NK cells against the K562 and NCI-H2087 cell lines was measured via calcein-release assay at E:T ratios of 10:1 to 0.5:1 in triplicate. (D) The NK cell degranulation activity was measured flow cytometrically with % of CD56+CD107a+ in coincubation with K562 cells (E:T ratio=1:1), with phorbol 12-myristate 13-acetate/ionomycin treatment (as positive control, P.C.), or without treatment (negative control, N.C.). Dots represent the mean value of each patient from 5 to 6 cultures for clinical trial. Horizontal bars indicate the mean value, and each point represents mean±standard deviation. NK, natural killer.

  • Fig. 3 Progression-free survival analysis. Kaplan-Meier analysis was used to estimate the progression-free survival of each cohort (A) or group patients who received natural killer cell infusion (B).


Reference

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