Abstract

While natural killer (NK) cell‐based adoptive transfer immunotherapy (ATI) provides only modest clinical success in cancer patients. This study was hypothesized that MRI‐guided transcatheter intra‐hepatic arterial (IHA) infusion permits local delivery to liver tumors to improve outcomes during NK‐based ATI in a rat model of hepatocellular carcinoma (HCC). Mouse NK cells were labeled with clinically applicable iron nanocomplexes. Twenty rat HCC models were assigned to three groups: transcatheter IHA saline infusion as the control group, transcatheter IHA NK infusion group, and intravenous (IV) NK infusion group. MRI studies were performed at baseline and at 24 h, 48 h, and 8 days postinfusion. There was a significant difference in tumor R2* values between baseline and 24 h following the selective transcatheter IHA NK delivery to the tumors (P = 0.039) when compared to IV NK infusion (P = 0.803). At 8 days postinfusion, there were significant differences in tumor volumes between the control, IV, and IHA NK infusion groups (control vs. IV, P = 0.196; control vs. IHA, P < 0.001; and IV vs. IHA, P = 0.001). Moreover, there was a strong correlation between tumor R2* value change (∆R2*) at 24 h postinfusion and tumor volume change (∆volume) at 8 days in IHA group (R 2 = 0.704, P < 0.001). Clinically applicable labeled NK cells with 12‐h labeling time can be tracked by MRI. Transcatheter IHA infusion improves NK cell homing efficacy and immunotherapeutic efficiency. The change in tumor R2* value 24 h postinfusion is an important early biomarker for prediction of longitudinal response.

Highlights

  • Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and the fourth leading cause of cancer death in the United States [1, 2]

  • Transcatheter intrahepatic arterial (IHA) infusion methods were described in previous studies [17,18,19]

  • Our study demonstrated the following: (1) clinically applicable HPF-­labeled natural killer (NK) can be tracked with magnetic resonance imaging (MRI), (2) transcatheter IHA NK infusion offers the potential to radically augment NK cell homing efficiency to liver tumors, and (3) the change of tumor R2* value at 24 h postinfusion is an important early biomarker for prediction of longitudinal response

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Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and the fourth leading cause of cancer death in the United States [1, 2]. The overall survival (OS) benefits from current liver-­directed transcatheter approaches remain relatively modest [2,3,4]. While natural killer (NK) cell-b­ased adoptive transfer immunotherapy (ATI) holds great promise for clinical cancer treatment, only modest clinical success has been achieved far using NK-­ATI therapies in cancer patients [5, 6]. We used a clinically applicable approach combining the FDA-­ approved drugs heparin, protamine, and MRI-­guided NK Cell for Cancer Treatment ferumoxytol to form HPF nanocomplexes for magnetic NK labeling so that NK cell biodistribution could be visualized in vivo with advanced magnetic resonance imaging (MRI) following transcatheter intrahepatic arterial (IHA) local delivery

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