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.