Sains Malaysiana 51(1)(2022): 271-284

http://doi.org/10.17576/jsm-2022-5101-22

A Safety Evaluation of Intravenous Administration of ex vivo Expanded Human Peripheral Blood-Derived NK Cells: A Preclinical Study

(Penilaian Keselamatan Pentadbiran ex vivo Sel NK Darah Janaan Periferi Manusia yang Dikembangkan secara Intravena: Kajian Praklinikal)

SELLAMUTHU SUBBANNA GOUNDER¹, BASKAR SUBRAMANI¹*, NUR EZZATI IZYAN BINTI MOHD RADZUANB¹, NURHIDAYAH BT MOHAMAD SAIT¹, FARAH DALILA BINTI MOHD ZAIN¹ & BASRI JOHAN JEET ABDULLAH²

¹Nichi-Asia Life Science Sdn Bhd, Kota Damansara PJU 5, 47810 Petaling Jaya, Selangor Darul Ehsan, Malaysia

²Department of Biomedical Imaging, University of Malaya, 50603 Kuala Lumpur, Federal Territory, Malaysia

Received:  19 January 2021/Accepted: 20 April 2021

ABSTRACT

The use of natural killer (NK) cells in the treatment of various cancers is emerging as a promising approach in adoptive immunotherapy. However, the safety of ex vivo activated and expanded cells in in vivo conditions remain unknown. In this study, the toxicity of NK cells was evaluated at different doses, with 5 × 10⁶, 20 × 10⁶ and 50 × 10⁶ cells injected intravenously into pre-irradiated (30Gy) immunodeficient mice twice a week for three weeks and the mice were followed-up on for 90 days. Throughout the study, no mortality, abnormal clinical signs, or behavioural changes related to the testing material were observed in either the treated or control groups of mice. There were no significant variations in food and water consumption between both genders in the NK cell treated and control groups. However, certain significant changes were observed between the groups in the clinical biochemistry and urine analysis reports. As autopsy showed no significant variations in absolute and relative organ weights between the groups, except for the livers of the treated mice. The histopathological analysis also demonstrated that there were no significant abnormalities in most of the organs of both genders, except for the liver. Some necrotic lesions were observed in the livers of both the treated and control mice, and these lesions may be due to the effects of irradiation or could be common in NOD.SCID mice. The findings of this study indicate that intravenous administration of NK cells is safe and does not cause any adverse effects up to the dose of 50 × 10⁶ cells/mouse.

Keywords: Adoptive immunotherapy; immunotherapy; natural killer cell; NK cell toxicity; pathology

ABSTRAK

Penggunaan sel pemusnah semula jadi (Natural Killer, NK) dalam rawatan pelbagai jenis kanser telah muncul sebagai pendekatan yang berpotensi dalam terapi imuno adoptif. Namun, keselamatan ex vivo teraktif dan sel berkembang dalam keadaan in vivo masih kekal tidak diketahui. Dalam kajian ini, ketoksikan sel NK telah disuntik secara intravena pada dos yang berbeza iaitu 5 × 10⁶, 20 × 10⁶ and 50 × 10⁶ kepada tikus keimunokurangan pre-tersinar (30Gy) sebanyak dua kali seminggu untuk 3 minggu dan tikus tersebut telah melalui pemeriksaan lanjutan untuk 90 hari. Sepanjang kajian ini, tiada kematian, tanda klinikal tidak normal atau perubahan tingkah laku berkait dengan bahan ujian dapat dilihat dalam mana-mana kumpulan tikus terawat atau terkawal. Tiada variasi yang jelas dalam pengambilan makanan dan air antara kedua dua jantina dalam kumpulan sel NK yang terawat dan terkawal. Namun, perbezaan perubahan yang jelas dapat dilihat antara kumpulan biokimia klinikal dan laporan analisis urin. Autopsi mendedahkan tiada perbezaan yang ketara pada variasi dalam berat organ mutlak dan relatif antara kumpulan, melainkan untuk hati tikus yang terawat. Analisis histopatologi juga menunjukkan bahawa tiada perbezaan yang ketara pada keabnormalan dalam kebanyakan organ untuk kedua-dua jantina, melainkan organ hati. Beberapa luka nekrosis dapat dilihat di dalam organ hati untuk kedua-dua tikus yang terawat dan terkawal, dan luka ini mungkin disebabkan oleh kesan penyinaran atau mungkin kesan biasa dalam tikus NOD.SCID. Penemuan kajian ini menunjukkan bahawa pemberian sel secara intravena NK adalah selamat dan tidak mengakibatkan kesan buruk sehingga dos 50 × 10⁶ sel/tikus.

Kata kunci: Ketoksikan sel NK; patologi; sel pemusnah semula jadi; terapi imuno; terapi imuno adoptif

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*Corresponding author; email: sudabas23@gmail.com