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Clinical Trial
. 2022 Jun 2:13:879452.
doi: 10.3389/fimmu.2022.879452. eCollection 2022.

A Phase I Study of Locoregional High-Dose Autologous Natural Killer Cell Therapy With Hepatic Arterial Infusion Chemotherapy in Patients With Locally Advanced Hepatocellular Carcinoma

Woo Kyun Bae  1   2 , Byung Chan Lee  3 , Hyeon-Jong Kim  1 , Je-Jung Lee  1   4 , Ik-Joo Chung  1   2 , Sung Bum Cho  5 , Yang Seok Koh  6
Affiliations
Clinical Trial

A Phase I Study of Locoregional High-Dose Autologous Natural Killer Cell Therapy With Hepatic Arterial Infusion Chemotherapy in Patients With Locally Advanced Hepatocellular Carcinoma

Woo Kyun Bae et al. Front Immunol. .

Abstract

Background: To explore the feasibility and safety of natural killer (NK) cell therapy in HCC, we performed a prospective, open-label, phase I trial to evaluate the synergistic effect of locoregional high-dose autologous NK cell therapy in combination with hepatic arterial infusion chemotherapy (HAIC).

Methods: Patients with locally advanced HCC who were refractory to the standard treatment were eligible for this study. Patients received expanded and activated NK cells for 5 consecutive days in a dose-escalating manner (dose 2.5×108, 5×108, 10×108 NK cells/injection) through hepatic arterial infusion following 4 cycles of HAIC with 5-fluorouracil (750 mg/m2) and cisplatin (25 mg/m2). The primary endpoint was the safety of NK cell-based immunotherapy, and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immunologic responses.

Results: Of the 11 patients enrolled, the confirmed ORR was 63.6% (complete response [CR]: 36.4%, confirmed partial response [PR]: 27.3%). Stable disease (SD) and progressive disease (PD) were observed in two patients (18.2%) each, resulting in a disease control rate (DCR) of 81.8%. The median PFS and OS were 10.3 and 41.6 months, respectively. There were no incidences of decompensation or severe adverse events during HAIC, and no adverse events related to NK cell infusion were noted.

Conclusion: The combination of HAIC and locoregional high-dose NK cell therapy is a safe and effective treatment for locally advanced HCC patients who were refractory to the standard treatment. This result warrants further development of this novel treatment to establish its efficacy in HCC.

Clinical trial registration: cris.nih.go.kr, identifier KCT0003973.

Keywords: autologous; clinical trial; hepatic arterial infusion chemotherapy (HAIC); hepatocellular carcinoma; natural killer (NK) cell.

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Conflict of interest statement

JL is employed by Vaxcell-Bio Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The schematic scheme for the treatment schedule of VAX-NK/HCC infusion following HAIC treatment. HAIC, hepatic arterial infusion chemotherapy; NK, natural killer; SCR, screening.
Figure 2
Figure 2
Kaplan-Meier estimates of survival outcomes. (A) progression-free survival. (B) overall survival. CI, confidence interval.
Figure 3
Figure 3
Time to progression and duration of response in patients with an objective response.
Figure 4
Figure 4
Changes in tumor marker levels during and after treatment. (A) α-fetoprotein (AFP) (IU/mL). (B) protein-induced by vitamin K absence or antagonist-II (PIVKA-II) (mAU/mL). NK, natural killer.
Figure 5
Figure 5
Immunoprofiling during and after treatment. (A) Percentages of peripheral NK cells with CD3-CD56+ before and after locoregional NK cell infusion. (B) The cytotoxic activity of PBMCs against K-562 cells at effector to a 10:1 E:T ratio. (C–E) The serum cytokine levels of IFN-γ, IL-10, and TGF-β.
See this image and copyright information in PMC

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