Background Hepatocellular carcinoma remains a leading cause of mortality worldwide, accounting for over three quarter of a million deaths annually.1 While transarterial chemoembolization (TACE) therapy is the current first-line intervention for the roughly 70–80% of cases which are non-resectable,2–6 repeated treatments quickly lead to recalcitrance in recurring tumors, and 5-year survival rates linger at an abysmal 18%.7 The results of our phase 1 trial indicated that autologous iNKT cell therapy has good tolerability in HCC patients and could potentially further improve outcomes.8
Methods This randomized, multicenter, open-label phase 2 trial was conducted at Beijing Youan, Beijing Shijitan, and Beijing Ditan Hospital of Capital Medical University between March 2018 and March 2020.Follow-up was completed on July 20, 2020. The cohort comprised 54 Barcelona Clinic Liver Cancer (BCLC) B/C stage patients with HCC after TACE failure. Efficacy analyses were conducted in the modified intention-to-treat population. Eligible patients were randomly assigned (1:1) to receive either transarterial embolization (TAE) therapy (TAE group) or a combination of TAE (weeks 0 and 4) plus iNKT cell infusion (6~9×107 cells/m2 intravenously) every 2 weeks starting week 1 (TAE-iNKT group). To exclude compromising iNKT cells, TAE was used instead of TACE. The primary endpoint was PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), peripheral blood cell count, and safety.
Results Fifty-four patients completed the study (table 1). Median PFS was significantly higher in TAE-iNKT patients (5.7 months [95% CI, 4.3–7.0 months]) compared with TAE patients (2.7 months [95% CI, 2.3–3.2 months]; hazard ratio 0.32 [95% CI, 0.16–0.63]; P<0.001) (figure 1). Higher objective response rate (ORR) and disease control rate (DCR) were observed in TAE-iNKT patients (52% and 85%, respectively) compared with TAE patients (11% and 33%; respectively)(table 2). Five TAE-iNKT patients and 1 TAE patient achieved completed response (figure 3). Median time to deterioration in QoL was longer in TAE-iNKT patients (9.2 months [95% CI, 6.0–13.3 months]) compared with TAE patients (3.0 months [95% CI, 2.9–3.0 months]) (figure 2). The mean lymphocytes were higher in the TAE-iNKT group than in the TAE group at 8 (1.48 vs. 0.95×109/L, P=.007) and 12 (1.49 vs. 0.89×109/L, P=.001) weeks (figure 4). Grade 3 adverse events occurred in 1 TAE-iNKT patient (4%) and 5 TAE patients (19%). All other adverse events were grade 1–2(table 3).
Conclusions iNKT cell infusion significantly improved PFS, ORR, DCR, and QoL with manageable toxicity during TAE therapy in patients with HCC.
Acknowledgements This study was funded by Capital Health Research and Development Projects (grant number: 2018-1-2181), the Original Exploration Program of the National Natural Science Foundation of China (grant number: 82150110), and the Beijing Municipal Administration of Hospitals Incubating Program (grant number: PX2019063). Nonfinancial support: iNKT cell was sponsored by the GeneKey GMP Lab.
Trial Registration ClinicalTrials.gov Identifier: NCT04011033
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Nov 2018;68(6):394−424.
Lafaro KJ, Demirjian AN, Pawlik TM. Epidemiology of hepatocellular carcinoma. Surgical oncology clinics of North America. Jan 2015;24(1):1−17.
Guidelines) NCPGiON. Hepatobiliary Cancers. National Comprehensive Cancer Network. 2020: Version 5. Fort Washington.
Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology: official journal of the European Society for Medical Oncology. Oct 1 2018;29(Suppl 4): iv238−iv255.
Kokudo N, Takemura N, Hasegawa K, et al. Clinical practice guidelines for hepatocellular carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatol Res. Oct 2019;49(10):1109−1113.
Chang PY, Huang CC, Hung CH, et al. Multidisciplinary Taiwan Consensus Recommendations for the Use of DEBDOX-TACE in Hepatocellular Carcinoma Treatment. Liver Cancer. Oct 2018;7(4):312−322.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a cancer journal for clinicians. Jan 2020;70(1):7−30.
Gao Y, Guo J, Bao X, et al. Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial. Oncologist. Nov 2021;26(11): e1919−e1930.
Ethics Approval The study protocol and consent form were approved by the ethics committee of Beijing Youan Hospital (Jing You Ke Lun  No. 016), and the other two participating units were subject to ethical examination and approval of the lead unit.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.