Autologous natural killer cell therapy for human recurrent malignant glioma.

TLDR

NK cells are potent tumor‑killing agents, yet clinical use in glioma is limited by difficulties in expanding autologous NK cells. The study evaluates adoptive immunotherapy with autologous NK cells expanded ex vivo for patients with recurrent malignant glioma. PBMCs were co‑cultured with irradiated feeder cells in RHAM‑alpha medium plus autologous plasma and IL‑2 to generate NK‑rich effector cells, which were then injected (focal and/or intravenous) into nine patients across 16 courses, with low‑dose interferon‑β as adjuvant. Across 16 courses, 3 partial responses, 2 mixed responses, 4 stable disease, and 7 progressive disease were observed, with no severe neurological toxicity, demonstrating that the ex vivo expansion and infusion of autologous NK cells is safe and partially effective in recurrent malignant glioma.

Abstract

Natural killer (NK) cells are highly efficient in the cellular immune response against malignant tumors without restriction of major histocompatibility complex. However clinical studies using autologous NK cells have been reported in only a very limited number of cases, due to the fact that selective NK expansion is difficult to achieve in this patient population. Here, we report the results of adoptive immunotherapy in patients with recurrent malignant gliomas using autologous NK cells that were expanded ex vivo by a novel method.Peripheral blood mononuclear cells (PBMCs) were prepared from patients with malignant gliomas, and were co-cultured with an irradiated human feeder cell line (HFWT) in RHAM-alpha medium supplemented with 5% autologous plasma and interleukin-2. The resulting NK cell-rich effector cells were injected into 9 patients (16 courses) with recurrent malignant glioma (6 cases of WHO grade-3 glioma and 3 cases of grade-4 glioma).The mean frequency of NK cells among lymphocytes was 82.2 +/- 10.5%. A combination of focal and intravenous injections was peformed in 10 courses. Intravenous injection alone was performed in 6 courses. Further, intravenous injection of low-dose interferon beta (6x10(6) IU/week) was performed as an adjuvant therapy in all courses to achieve maximum benefit for enrolled patients. Clinical evaluation demonstrated 3 PR, 2 MR, 4 NC and 7 PD in a total of 16 courses of treatment. Severe neurological toxicity was not observed in any of the patients.It was demonstrated that NK cell-rich effector cells were expanded ex vivo from PBMCs in all nine cases of recurrent malignant glioma and that NK cell therapy was safe and partially effective in patients with recurrent malignant gliomas.