Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial.
LESSONS LEARNED
Administration of autologous invariant natural killer T (iNKT) cells was safe and well-tolerated in patients with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage B/C). Expanded iNKT cells produced T-helper 1-like responses with possible antitumor activity. No severe adverse events were observed in any of the enrolled patients, including one patient who received 1010 in vitro-expanded autologous iNKT cells as a single infusion.


BACKGROUND
Invariant natural killer T cells co-express T-cell antigen receptor and natural killer (NK) cell receptors. Invariant natural killer T (iNKT) cells exhibit antitumor activity, but their numbers and functions are impaired in patients with hepatocellular carcinoma (HCC). The adoptive transfer of iNKT cells might treat advanced HCC.


METHODS
This phase I study (NCT03175679) enrolled 10 patients with HCC (Barcelona Clinic Liver Cancer [BCLC] stage B/C) at Beijing YouAn Hospital (April 2017 to May 2018). iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) were expanded and alpha-galactosylceramide (α-GalCer)-pulsed. Dosage escalated from 3 × 107 to 6 × 107 to 9 × 107 cells/m2 (3+3 design). An exploratory dose trial (1 × 1010 cells/m2 ) was conducted in one patient.


RESULTS
Expanded iNKT cells produced greater quantities of T-helper 1 (Th1) cytokines (e.g., interferon-gamma, perforin, and granzyme B) but less interleukin-4 than nonexpanded iNKT cells. Circulating numbers of iNKT cells and activated NK cells were increased after iNKT cell infusion. Most treatment-related adverse events were grade 1-2, and three grade 3 adverse events were reported; all resolved without treatment. Four patients were progression-free at 5.5, 6, 7, and 11 months after therapy, and one patient was alive and without tumor recurrence at the last follow-up. Five patients died at 1.5 to 11 months after treatment.


CONCLUSION
Autologous iNKT cell treatment is safe and well-tolerated. Expanded iNKT cells produce Th1-like responses with possible antitumor activity. The antitumor effects of iNKT cell infusion in patients with advanced HCC merit further investigation.
['Gao|Yao|Y|', 'Guo|Jia|J|', 'Bao|Xuli|X|', 'Xiong|Fang|F|', 'Ma|Yanpin|Y|', 'Tan|Bingqin|B|', 'Yu|Lele|L|', 'Zhao|Yong|Y|', 'Lu|Jun|J|https://orcid.org/0000-0002-1269-9678']
Natural killer T cells Immunotherapy Hepatocellular carcinoma