Autologous natural killer cell therapy for human recurrent malignant glioma.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Ishikawa
Eiichi
E
Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Science City, Ibaraki 305-8575, Japan.
Tsuboi
Koji
K
Saijo
Kaoru
K
Harada
Hideki
H
Takano
Shingo
S
Nose
Tadao
T
Ohno
Tadao
T
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D018920:Coculture Techniques; D005260:Female; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016899:Interferon-beta / Q000627:therapeutic use; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy*
D007376:Interleukin-2; D016899:Interferon-beta