Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
권호 표지
DOI QR코드

DOI QR Code

A general toxicity and biodistribution study of human natural killer cells by single or repeated intravenous dose in severe combined immune deficient mice

  • Park, Sang-Jin (Department of Toxicological Evaluation and Research, Korea Institute of Toxicology) ;
  • Yoon, Hae-Jin (Department of Toxicological Evaluation and Research, Korea Institute of Toxicology) ;
  • Gu, Eun-Young (Department of Toxicological Evaluation and Research, Korea Institute of Toxicology) ;
  • Lee, Byoung-Seok (Department of Toxicological Evaluation and Research, Korea Institute of Toxicology) ;
  • Kim, Yongman (NKMAX Co., Ltd) ;
  • Jung, Jaeseob (NKMAX Co., Ltd) ;
  • Kim, Jinmoon (NKMAX Co., Ltd) ;
  • Moon, Kyoung-Sik (Department of Toxicological Evaluation and Research, Korea Institute of Toxicology)
  • Received : 2022.02.16
  • Accepted : 2022.05.11
  • Published : 2022.10.15
⟨ Previous Next ⟩

Abstract

Natural killer (NK) cells are a part of the innate immune system and represent the first line of defense against infections and tumors. NK cells can eliminate tumor cells without major histocompatibility restriction and are independent of the expression of tumor-associated antigens. Therefore, they are considered an emerging tool for cancer immunotherapy. However, the general toxicity and biodistribution of NK cells after transplantation remain to be understood. This study was conducted to evaluate the general toxicity and biodistribution of human NK cells after single or repeated intravenous dosing in severely combined immunodeficient (SCID) mice. There were no test item-related toxicological changes in single and repeated administration groups. The no observed adverse effect level of human NK cells was 2×107 cells/head for both male and female SCID mice. Results from the biodistribution study showed that human NK cells were mainly distributed in the lungs, and a small number of the cells were detected in the liver, heart, spleen, and kidney of SCID mice, in both the single and repeated dose groups. Additionally, human NK cells were completely eliminated from all organs of the mice in the single dose group on day 7, while the cells persisted in mice in the repeated dose group until day 64. In conclusion, transplantation of human NK cells in SCID mice had no toxic effects. The cells were mainly distributed in the lungs and completely disappeared from the body over time after single or repeated intravenous administration.

Keywords

Acknowledgement

This work was supported by Korea Institute of Toxicology Research Program (KK-2212).

References

  1. Hu Y, Tian Z, Zhang C (2019) Natural killer cell-based immunotherapy for cancer: advances and prospects. Eng 5:106-114. https://doi.org/10.1016/j.eng.2018.11.015
  2. Cheng M, Chen Y, Xiao W, Sun R, Tian Z (2013) NK cellbased immunotherapy for malignant diseases. Cell Mol Immunol 10:230-252. https://doi.org/10.1038/cmi. 2013. 10
  3. Kim S, Iizuka K, Aguila HL, Weissman IL, Yokoyama WM (2000) In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA 97:2731-2736. https://doi.org/10.1073/pnas.050588297
  4. Smyth MJ, Hayakawa Y, Takeda K, Yagita H (2002) New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2:850-861. https://doi.org/10.1038/nrc928
  5. Handgretinger R, Lang P, Andre MC (2016) Exploitation of natural killer cells for the treatment of acute leukemia. Blood 127:3341-3349. https://doi.org/10.1182/blood-2015-12-629055
  6. He Y, Tian Z (2017) NK cell education via nonclassical MHC and non-MHC ligands. Cell Mol Immunol 14:321-330. https://doi.org/10.1038/cmi.2016.26
  7. Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL et al (2012) Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One 7:e30264. https://doi.org/10.1371/journal.pone.0030264
  8. Luevano M, Daryouzeh M, Alnabhan R, Querol S, Khakoo S, Madrigal A et al (2012) The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation. Hum Immunol 73:248-257. https://doi.org/10.1016/j.humimm.2011.12.015
  9. Dalle JH, Menezes J, Wagner E, Blagdon M, Champagne J, Champagne MA et al (2005) Characterization of cord blood natural killer cells: implications for transplantation and neonatal infections. Pediatr Res 57:649-655. https://doi.org/10.1203/01.PDR.0000156501.55431.20
  10. Rengasamy M, Gupta PK, Kolkundkar U, Singh G, Balasubramanian S, Sundarraj S et al (2016) Preclinical safety & toxicity evaluation of pooled, allogeneic human bone marrow-derived mesenchymal stromal cells. Indian J Med Res 144:852-864. https://doi.org/10.4103/ijmr.IJMR_1842_15
  11. Geller MA, Cooley S, Judson PL, Ghebre R, Carson LF, Argenta PA et al (2011) A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13:98-107. https://doi.org/10.3109/14653249.2010.515582
  12. Childs RW, Carlsten M (2015) Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. Nat Rev Drug Discov 14:487-498. https://doi.org/10.1038/nrd4506
  13. Lim SA, Kim TJ, Lee JE, Sonn CH, Kim K, Kim J et al (2013) Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Cancer Res 73:2598-2607. https://doi.org/10.1158/0008-5472.CAN-12-2893
  14. Nicklas JA, Buel E (2003) Development of an Alu-based, realtime PCR method for quantitation of human DNA in forensic samples. J Forensic Sci 48:936-944. https://doi.org/10.1520/JFS2002414
  15. Raghunathan S, Reynolds CL, Stewart MD, Schwartz RJ, McConnell BK (2017) Spontaneous dystrophic cardiac calcinosis in CB-17 SCID mice. FASEB J 31:1070
  16. Kato C, Fujii E, Chen YJ, Endaya BB, Matsubara K, Suzuki M et al (2009) Spontaneous thymic lymphomas in the non-obese diabetic/Shi-scid, IL-2R gamma null mouse. Lab Anim 43:402-404. https://doi.org/10.1258/la.2009.009012
  17. Brehm C, Huenecke S, Quaiser A, Esser R, Bremm M, Kloess S et al (2011) IL-2 stimulated but not unstimulated NK cells induce selective disappearance of peripheral blood cells: concomitant results to a phase I/II study. PLoS One 6:e27351. https://doi.org/10.1371/journal.pone.0027351
  18. Koehl U, Brehm C, Huenecke S, Zimmermann SY, Kloess S, Bremm M, Ullrich E, Soerensen J, Quaiser A, Erben S, Wunram C, Gardlowski T, Auth E, Tonn T, Seidl C, Meyer-Monard S, Stern M, Passweg J, Klingebiel T, Bader P, Schwabe D, Esser R (2013) Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Front Oncol 3:118. https://doi.org/10.3389/fonc.2013.00118
  19. Linn YC, Yong HX, Niam M, Lim TJ, Chu S, Choong A et al (2012) A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission. Cytotherapy 14:851-859. https://doi.org/10.3109/14653249.2012.694419
  20. Suen WC-W, Lee WY-W, Leung KT, Pan XH, Li G (2018) Natural killer cell-based cancer immunotherapy: a review on 10 years completed clinical trials. Cancer Investig 36:431-457. https://doi.org/10.1080/07357907.2018.1515315
  21. Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA et al (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210:474-484 discussion 484. https://doi.org/10.1097/00000658-198910000-00008
  22. Oh S, Lee JH, Kwack K, Choi SW (2019) Natural killer cell therapy: a new treatment paradigm for solid tumors. Cancers 11:1534. https://doi.org/10.3390/cance rs111 01534
  23. Bolourian A, Mojtahedi Z (2017) Possible damage to immuneprivileged sites in natural killer cell therapy in cancer patients: side effects of natural killer cell therapy. Immunotherapy 9:281-288. https://doi.org/10.2217/imt-2016-0137
  24. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169:12-20. https://doi.org/10.1159/000047856
  25. Meyerrose TE, De Ugarte DA, Hofling AA, Herrbrich PE, Cordonnier TD, Shultz LD et al (2007) In vivo distribution of human adipose-derived mesenchymal stem cells in novel xenotransplantation models. Stem Cells 25:220-227. https://doi.org/10.1634/stemcells.2006-0243
  26. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI et al (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683-692. https://doi.org/10.1089/scd. 2008.0253