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Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK

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Abstract

Purpose

High-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.

Methods

iNSCs cells expressing HSV-TK (iNSCsTK) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCsTK and the combinational therapeutics of iNSCsTK and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.

Results

PBMC-derived iNSCsTK possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCsTK/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCsTK/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.

Conclusions

PBMC-derived iNSCsTK showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCsTK therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

GBM:

Glioblastoma,

HSV-TK:

Herpes simplex virus thymidine kinase,

CNS:

Cancers of the central nervous system,

EGFP:

Enhanced green fluorescent protein,

CAR:

Chimeric antigen receptors,

iNSCs:

Inducing neural stem cells,

LDH:

Lactate dehydrogenase,

PI:

Propidium iodide,

GD2:

Disialoganglioside,

NK cell:

Natural killing cell,

GCV:

Ganciclovir,

HNA:

Human nuclei antigen,

GVHD:

Graft-vs-host-disease,

HMGB1:

High mobility group box 1protein

References

  1. R. Medikonda, G. Dunn, M. Rahman, P. Fecci, M. Lim, A review of glioblastoma immunotherapy. J. Neurooncol. 151(1), 41–53 (2021)

    Article  PubMed  Google Scholar 

  2. W. Tomaszewski, L. Sanchez-Perez, T.F. Gajewski, J.H. Sampson, Brain Tumor Microenvironment and Host State: Implications for Immunotherapy. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 25(14), 4202–4210 (2019)

    Article  CAS  Google Scholar 

  3. V. Rajaratnam, M.M. Islam, M. Yang, R. Slaby, H.M. Ramirez, S.P. Mirza, Glioblastoma: Pathogenesis and current status of chemotherapy and other novel treatments. Cancers (Basel). 12(4):937 (2020)

  4. G. Minniti, M. Niyazi, F. Alongi, P. Navarria, C. Belka, Current status and recent advances in reirradiation of glioblastoma. Radiat. Oncol. (London, England) 16(1), 36 (2021)

    Article  Google Scholar 

  5. S. Li, T. Tokuyama, J. Yamamoto, M. Koide, N. Yokota, H. Namba, Potent bystander effect in suicide gene therapy using neural stem cells transduced with herpes simplex virus thymidine kinase gene. Oncology 69(6), 503–508 (2005)

    Article  PubMed  Google Scholar 

  6. E. Preuss, A. Treschow, S. Newrzela, D. Brücher, K. Weber, U. Felldin, E. Alici, G. Gahrton, D. von Laer, M.S. Dilber et al., TK.007: A novel, codon-optimized HSVtk(A168H) mutant for suicide gene therapy. Hum. Gene Ther. 21(8), 929–941 (2010)

    Article  CAS  PubMed  Google Scholar 

  7. E. Preuss, A. Muik, K. Weber, J. Otte, D. von Laer, B. Fehse, Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect. J. Mol. Med. (Berl) 89(11), 1113–1124 (2011)

    Article  CAS  PubMed  Google Scholar 

  8. S. Li, T. Tokuyama, J. Yamamoto, M. Koide, N. Yokota, H. Namba, Bystander effect-mediated gene therapy of gliomas using genetically engineered neural stem cells. Cancer Gene Ther. 12(7), 600–607 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. N.G. Rainov, A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther. 11(17), 2389–2401 (2000)

    Article  CAS  PubMed  Google Scholar 

  10. K.S. Aboody, A. Brown, N.G. Rainov, K.A. Bower, S. Liu, W. Yang, J.E. Small, U. Herrlinger, V. Ourednik, P.M. Black et al., Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc. Natl. Acad. Sci. U.S.A. 97(23), 12846–12851 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. R. Mooney, M. Hammad, J. Batalla-Covello, A. Abdul Majid, K.S. Aboody, Concise review: neural stem cell-mediated targeted cancer therapies. Stem Cells Transl. Med. 7(10), 740–747 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  12. D. Zhao, J. Najbauer, E. Garcia, M.Z. Metz, M. Gutova, C.A. Glackin, S.U. Kim, K.S. Aboody, Neural stem cell tropism to glioma: critical role of tumor hypoxia. Mol. Cancer Res.: MCR 6(12), 1819–1829 (2008)

    Article  CAS  PubMed  Google Scholar 

  13. M.Z. Metz, M. Gutova, S.F. Lacey, Y. Abramyants, T. Vo, M. Gilchrist, R. Tirughana, L.Y. Ghoda, M.E. Barish, C.E. Brown et al., Neural stem cell-mediated delivery of irinotecan-activating carboxylesterases to glioma: implications for clinical use. Stem Cells Transl. Med. 2(12), 983–992 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. K.S. Aboody, J. Najbauer, M.Z. Metz, M. D’Apuzzo, M. Gutova, A.J. Annala, T.W. Synold, L.A. Couture, S. Blanchard, R.A. Moats et al., Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies. Sci. Transl. Med. 5(184), 184ra159 (2013)

    Article  Google Scholar 

  15. R. Mooney, A. Abdul Majid, J. Batalla, A.J. Annala, K.S. Aboody, Cell-mediated enzyme prodrug cancer therapies. Adv. Drug Deliv. Rev. 118, 35–51 (2017)

    Article  CAS  PubMed  Google Scholar 

  16. K. Takahashi, S. Yamanaka, Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4), 663–676 (2006)

    Article  CAS  PubMed  Google Scholar 

  17. K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, S. Yamanaka, Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5), 861–872 (2007)

    Article  CAS  PubMed  Google Scholar 

  18. R. Tamura, H. Miyoshi, Y. Morimoto, Y. Oishi, O. Sampetrean, C. Iwasawa, Y. Mine, H. Saya, K. Yoshida, H. Okano et al., Gene therapy using neural stem/progenitor cells derived from human induced pluripotent stem cells: visualization of migration and bystander killing effect. Hum. Gene Ther. 31(5–6), 352–366 (2020)

    Article  CAS  PubMed  Google Scholar 

  19. J.R. Bagó, O. Okolie, R. Dumitru, M.G. Ewend, J.S. Parker, R.V. Werff, T.M. Underhill, R.S. Schmid, C.R. Miller, S.D. Hingtgen, Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Sci. Transl. Med. 9(375), (2017)

  20. M. Thier, P. Wörsdörfer, Y.B. Lakes, R. Gorris, S. Herms, T. Opitz, D. Seiferling, T. Quandel, P. Hoffmann, M.M. Nöthen et al., Direct conversion of fibroblasts into stably expandable neural stem cells. Cell Stem Cell 10(4), 473–479 (2012)

    Article  CAS  PubMed  Google Scholar 

  21. E. Lujan, S. Chanda, H. Ahlenius, T.C. Südhof, M. Wernig, Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc. Natl. Acad. Sci. U.S.A. 109(7), 2527–2532 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. A.B. Satterlee, D.E. Dunn, D.C. Lo, S. Khagi, S. Hingtgen, Tumoricidal stem cell therapy enables killing in novel hybrid models of heterogeneous glioblastoma. Neuro Oncol. 21(12), 1552–1564 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. S. Suman, A. Domingues, J. Ratajczak, M.Z. Ratajczak, Potential clinical applications of stem cells in regenerative medicine. Adv. Exp. Med. Biol. 1201, 1–22 (2019)

    Article  CAS  PubMed  Google Scholar 

  24. Y. Yuan, X. Tang, Y.F. Bai, S. Wang, J. An, Y. Wu, Z.D. Xu, Y.A. Zhang, Z. Chen, Dopaminergic precursors differentiated from human blood-derived induced neural stem cells improve symptoms of a mouse Parkinson’s disease model. Theranostics 8(17), 4679–4694 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. A.L. Mende, J.D. Schulte, H. Okada, J.L. Clarke, Current Advances in Immunotherapy for Glioblastoma. Curr. Oncol. Rep. 23(2), 21 (2021)

    Article  PubMed  PubMed Central  Google Scholar 

  26. M.W. Yu, D.F. Quail, Immunotherapy for glioblastoma: current progress and challenges. Front. Immunol. 12, 676301 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. M. Martinez, E.K. Moon, CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front. Immunol. 10, 128 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. R. Ma, T. Lu, Z. Li, K.Y. Teng, A.G. Mansour, M. Yu, L. Tian, B. Xu, S. Ma, J. Zhang et al., An oncolytic virus expressing IL15/IL15Rα combined with Off-the-Shelf EGFR-CAR NK cells targets glioblastoma. Can. Res. 81(13), 3635–3648 (2021)

    Article  CAS  Google Scholar 

  29. M. Prapa, C. Chiavelli, G. Golinelli, G. Grisendi, M. Bestagno, R. Di Tinco, M. Dall’Ora, G. Neri, O. Candini, C. Spano et al., GD2 CAR T cells against human glioblastoma. NPJ Precis. Oncol. 5(1), 93 (2021)

    Article  PubMed  PubMed Central  Google Scholar 

  30. T. Gargett, L.M. Ebert, N.T.H. Truong, P.M. Kollis, K. Sedivakova, W. Yu, E.C.F. Yeo, N.L. Wittwer, B.L. Gliddon, M.N. Tea et al., GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma. J Immunother Cancer. 10(9), e005187 (2022)

  31. M.C. Burger, C. Zhang, P.N. Harter, A. Romanski, F. Strassheimer, C. Senft, T. Tonn, J.P. Steinbach, W.S. Wels, CAR-Engineered NK cells for the treatment of glioblastoma: turning innate effectors into precision tools for cancer immunotherapy. Front. Immunol. 10, 2683 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. M. Gang, N.D. Marin, P. Wong, C.C. Neal, L. Marsala, M. Foster, T. Schappe, W. Meng, J. Tran, M. Schaettler et al., CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas. Blood 136(20), 2308–2318 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  33. A. Balatsoukas, F. Rossignoli, K. Shah, NK cells in the brain: implications for brain tumor development and therapy. Trends Mol. Med. 28(3), 194–209 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Y. Zhao, Z. Liu, X. Wang, H. Wu, J. Zhang, J. Yang, F. Zhang, L. Liu, J. Long, P. Lu et al., Treatment with humanized selective CD19CAR-T cells shows efficacy in highly treated B-ALL patients who have relapsed after receiving murine-based CD19CAR-T therapies. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 25(18), 5595–5607 (2019)

    Article  CAS  Google Scholar 

  35. S. Charrier, M. Ferrand, M. Zerbato, G. Précigout, A. Viornery, S. Bucher-Laurent, S. Benkhelifa-Ziyyat, O.W. Merten, J. Perea, A. Galy, Quantification of lentiviral vector copy numbers in individual hematopoietic colony-forming cells shows vector dose-dependent effects on the frequency and level of transduction. Gene Ther. 18(5), 479–487 (2011)

    Article  CAS  PubMed  Google Scholar 

  36. J.R. Bago, A. Alfonso-Pecchio, O. Okolie, R. Dumitru, A. Rinkenbaugh, A.S. Baldwin, C.R. Miller, S.T. Magness, S.D. Hingtgen, Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat. Commun. 7, 10593 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. C. Zhang, M.C. Burger, L. Jennewein, S. Genßler, K. Schönfeld, P. Zeiner, E. Hattingen, P.N. Harter, M. Mittelbronn, T. Tonn et al., ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma. J Natl Cancer Inst. 108(5) (2016)

  38. S. Murty, S.T. Haile, C. Beinat, A. Aalipour, I.S. Alam, T. Murty, T.M. Shaffer, C.B. Patel, E.E. Graves, C.L. Mackall et al., Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model. Oncoimmunology 9(1), 1757360 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  39. J. Portnow, T.W. Synold, B. Badie, R. Tirughana, S.F. Lacey, M. D’Apuzzo, M.Z. Metz, J. Najbauer, V. Bedell, T. Vo et al., Neural stem cell-based anticancer gene therapy: a first-in-human study in recurrent high-grade glioma patients. Clin. Cancer Res.: Off. J. Am. Assoc. Cancer Res. 23(12), 2951–2960 (2017)

    Article  CAS  Google Scholar 

  40. Y. Kimura, T. Shofuda, Y. Higuchi, I. Nagamori, M. Oda, M. Nakamori, M. Onodera, D. Kanematsu, A. Yamamoto, A. Katsuma et al., Human genomic safe harbors and the suicide gene-based safeguard system for iPSC-Based cell therapy. Stem Cells Transl. Med. 8(7), 627–638 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. C.M. Jackson, J. Choi, M. Lim, Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat. Immunol. 20(9), 1100–1109 (2019)

    Article  CAS  PubMed  Google Scholar 

  42. D.M. O'Rourke, M.P. Nasrallah, A. Desai, J.J. Melenhorst, K. Mansfield, J.J.D. Morrissette, M. Martinez-Lage, S. Brem, E. Maloney, A. Shen et al., A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 9(399), eaaa0984 (2017)

  43. S.L. Goff, R.A. Morgan, J.C. Yang, R.M. Sherry, P.F. Robbins, N.P. Restifo, S.A. Feldman, Y.C. Lu, L. Lu, Z. Zheng et al., Pilot trial of adoptive transfer of chimeric antigen receptor-transduced T cells targeting EGFRvIII in patients with glioblastoma. J. Immunother. (Hagerstown, Md : 1997) 42(4), 126–135 (2019)

    CAS  Google Scholar 

  44. C. Zhang, P. Oberoi, S. Oelsner, A. Waldmann, A. Lindner, T. Tonn, W.S. Wels, Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front. Immunol. 8, 533 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  45. M. Chrobok, C.I.M. Dahlberg, E.C. Sayitoglu, V. Beljanski, H. Nahi, M. Gilljam, B. Stellan, T. Sutlu, A.D. Duru, E. Alici., Functional assessment for clinical use of serum-free adapted NK-92 cells. Cancers (Basel). 11(1), 69 (2019)

  46. S. Arai, R. Meagher, M. Swearingen, H. Myint, E. Rich, J. Martinson, H. Klingemann, Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 10(6), 625–632 (2008)

    Article  CAS  PubMed  Google Scholar 

  47. R. Tamura, H. Miyoshi, K. Yoshida, H. Okano, M. Toda, Recent progress in the research of suicide gene therapy for malignant glioma. Neurosurg. Rev. 44(1), 29–49 (2021)

    Article  PubMed  Google Scholar 

  48. R.L. Touraine, H. Ishii-Morita, W.J. Ramsey, R.M. Blaese, The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication. Gene Ther. 5(12), 1705–1711 (1998)

    Article  CAS  PubMed  Google Scholar 

  49. P. Maleki Dana, F. Sadoughi, H. Mirzaei, Z. Asemi, B. Yousefi, DNA damage response and repair in the development and treatment of brain tumors. Eur. J. Pharmacol. 924, 174957 (2022)

    Article  CAS  PubMed  Google Scholar 

  50. S. Bao, Q. Wu, R.E. McLendon, Y. Hao, Q. Shi, A.B. Hjelmeland, M.W. Dewhirst, D.D. Bigner, J.N. Rich, Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120), 756–760 (2006)

    Article  CAS  PubMed  Google Scholar 

  51. A.B.L. Colamartino, W. Lemieux, P. Bifsha, S. Nicoletti, N. Chakravarti, J. Sanz, H. Roméro, S. Selleri, K. Béland, M. Guiot et al., Efficient and robust NK-Cell transduction with baboon envelope Pseudotyped Lentivector. Front. Immunol. 10, 2873 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Y. Ge, L. Chen, S. Liu, J. Zhao, H. Zhang, P.R. Chen, Enzyme-mediated intercellular proximity labeling for detecting cell-cell interactions. J. Am. Chem. Soc. 141(5), 1833–1837 (2019)

    Article  CAS  PubMed  Google Scholar 

  53. M. Candolfi, K. Yagiz, D. Foulad, G.E. Alzadeh, M. Tesarfreund, A.K. Muhammad, M. Puntel, K.M. Kroeger, C. Liu, S. Lee et al., Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Clin. Cancer Res: Off. J Am. Assoc. Cancer Res. 15(13), 4401–4414 (2009)

    Article  CAS  Google Scholar 

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Funding

This work was supported by National Natural Science Foundation of China (81973351, 82171250 and 82173840). Beijing Talents Foundation (2017000021223TD03), Beijing Municipal Health Commission Fund (PXM2020_026283_000005).

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Author notes

  1. Weihua Liu and Yu Zhao contributed equally to this work.

Authors and Affiliations

  1. Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China

    Weihua Liu, Yu Zhao, Zhongfeng Liu, Guangji Zhang, Huantong Wu, Xin Zheng & Zhiguo Chen

  2. Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, 100069, China

    Weihua Liu, Yu Zhao, Zhongfeng Liu, Guangji Zhang, Huantong Wu, Xin Zheng & Zhiguo Chen

  3. Neurosurgery Center of Aeronautical General Hospital, Beijing, 100012, China

    Xihe Tang

  4. Beijing, China

    Zhiguo Chen

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  1. Weihua Liu
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Contributions

Z.C., W.L., Y.Z. and X.T. contributed to the conception and experimental designs; W.L., Y.Z., Z.L., G.Z., H.W., and X.Z. did the experiments and analyzed the data; W.L., Y.Z., Z.L., G.Z., H.W., and X.Z. collected the samples; W.L., Y.Z. and Z.C. wrote and revised the manuscript. Z.C. secured funding and supervised the study. All authors have read the manuscript and approved the final version.

Corresponding author

Correspondence to Zhiguo Chen.

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All Procedures performed in studies involving animals were approved by the Ethics Committee of Xuanwu hospital capital medical university. All the mouse experimental procedures were performed according to the protocols approved by the Xuanwu hospital capital medical university Experimental Animal Care Commission.

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Liu, W., Zhao, Y., Liu, Z. et al. Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK. Cell Oncol. 46, 1747–1762 (2023). https://doi.org/10.1007/s13402-023-00842-5

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