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Optimized human CYP4B1 in combination with the alkylator prodrug 4-ipomeanol serves as a novel suicide gene system for adoptive T-cell therapies

Gene Therapy volume 23, pages 615–626 (2016)Cite this article

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Abstract

Engineering autologous or allogeneic T cells to express a suicide gene can control potential toxicity in adoptive T-cell therapies. We recently reported the development of a novel human suicide gene system that is based on an orphan human cytochrome P450 enzyme, CYP4B1, and the naturally occurring alkylator prodrug 4-ipomeanol. The goal of this study was to systematically develop a clinically applicable self-inactivating lentiviral vector for efficient co-expression of CYP4B1 as an ER-located protein with two distinct types of cell surface proteins, either MACS selection genes for donor lymphocyte infusions after allogeneic stem cell transplantation or chimeric antigen receptors for retargeting primary T cells. The U3 region of the myeloproliferative sarcoma virus in combination with the T2A site was found to drive high-level expression of our CYP4B1 mutant with truncated CD34 or CD271 as MACS suitable selection markers. This lentiviral vector backbone was also well suited for co-expression of CYP4B1 with a codon-optimized CD19 chimeric antigen receptor (CAR) construct. Finally, 4-ipomeanol efficiently induced apoptosis in primary T cells that co-express mutant CYP4B1 and the divergently located MACS selection and CAR genes. In conclusion, we here developed a clinically suited lentiviral vector that supports high-level co-expression of cell surface proteins with a potent novel human suicide gene.

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References

  1. Stauss HJ, Cesco-Gaspere M, Thomas S, Hart DP, Xue SA, Holler A et al. Monoclonal T-cell receptors: new reagents for cancer therapy. Mol Ther 2007; 15: 1744–1750.

    Article  CAS  PubMed  Google Scholar 

  2. Dotti G, Gottschalk S, Savoldo B, Brenner MK . Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev 2014; 257: 107–126.

    Article  CAS  PubMed  Google Scholar 

  3. Maus MV, Fraietta JA, Levine BL, Kalos M, Zhao Y, June CH . Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol 2014; 32: 189–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Restifo NP, Dudley ME, Rosenberg SA . Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 2012; 12: 269–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sadelain M, Brentjens R, Riviere I . The promise and potential pitfalls of chimeric antigen receptors. Curr Opin Immunol 2009; 21: 215–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 2011; 118: 6050–6056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 2008; 14: 1264–1270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509–1518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014; 371: 1507–1517.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Porter DL, Levine BL, Kalos M, Bagg A, June CH . Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365: 725–733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 2011; 118: 4817–4828.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 2012; 119: 2709–2720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chinnasamy N, Wargo JA, Yu Z, Rao M, Frankel TL, Riley JP et al. A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol 2011; 186: 685–696.

    Article  CAS  PubMed  Google Scholar 

  14. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 2013; 122: 863–871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013; 36: 133–151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997; 276: 1719–1724.

    Article  CAS  PubMed  Google Scholar 

  17. Cieri N, Mastaglio S, Oliveira G, Casucci M, Bondanza A, Bonini C . Adoptive immunotherapy with genetically modified lymphocytes in allogeneic stem cell transplantation. Immunol Rev 2014; 257: 165–180.

    Article  CAS  PubMed  Google Scholar 

  18. Tiberghien P, Ferrand C, Lioure B, Milpied N, Angonin R, Deconinck E et al. Administration of herpes simplex-thymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 2001; 97: 63–72.

    Article  CAS  PubMed  Google Scholar 

  19. Garin MI, Garrett E, Tiberghien P, Apperley JF, Chalmers D, Melo JV et al. Molecular mechanism for ganciclovir resistance in human T lymphocytes transduced with retroviral vectors carrying the herpes simplex virus thymidine kinase gene. Blood 2001; 97: 122–129.

    Article  CAS  PubMed  Google Scholar 

  20. Berger C, Flowers ME, Warren EH, Riddell SR . Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 2006; 107: 2294–2302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 2011; 365: 1673–1683.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Freytag SO, Khil M, Stricker H, Peabody J, Menon M, DePeralta-Venturina M et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002; 62: 4968–4976.

    CAS  PubMed  Google Scholar 

  23. Junker K, Koehl U, Zimmerman S, Stein S, Schwabe D, Klingebiel T et al. Kinetics of cell death in T lymphocytes genetically modified with two novel suicide fusion genes. Gene Ther 2003; 10: 1189–1197.

    Article  CAS  PubMed  Google Scholar 

  24. Zhan H, Gilmour K, Chan L, Farzaneh F, McNicol AM, Xu JH et al. Production and first-in-man use of T cells engineered to express a HSVTK-CD34 sort-suicide gene. PLoS ONE 2013; 8: e77106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wiek C, Schmidt EM, Roellecke K, Freund M, Nakano M, Kelly EJ et al. Identification of amino acid determinants in CYP4B1 for optimal catalytic processing of 4-ipomeanol. Biochem J 2015; 465: 103–114.

    Article  CAS  PubMed  Google Scholar 

  26. Baer BR, Rettie AE . CYP4B1: an enigmatic P450 at the interface between xenobiotic and endobiotic metabolism. Drug Metab Rev 2006; 38: 451–476.

    Article  CAS  PubMed  Google Scholar 

  27. Nelson DR . The cytochrome p450 homepage. Hum Genomics 2009; 4: 59–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kasturi VK, Dearing MP, Piscitelli SC, Russell EK, Sladek GG, O'Neil K et al. Phase I study of a five-day dose schedule of 4-Ipomeanol in patients with non-small cell lung cancer. Clin Cancer Res 1998; 4: 2095–2102.

    CAS  PubMed  Google Scholar 

  29. Lakhanpal S, Donehower RC, Rowinsky EK . Phase II study of 4-ipomeanol, a naturally occurring alkylating furan, in patients with advanced hepatocellular carcinoma. Invest New Drugs 2001; 19: 69–76.

    Article  CAS  PubMed  Google Scholar 

  30. Czerwinski M, McLemore TL, Philpot RM, Nhamburo PT, Korzekwa K, Gelboin HV et al. Metabolic activation of 4-ipomeanol by complementary DNA-expressed human cytochromes P-450: evidence for species-specific metabolism. Cancer Res 1991; 51: 4636–4638.

    CAS  PubMed  Google Scholar 

  31. Zheng YM, Henne KR, Charmley P, Kim RB, McCarver DG, Cabacungan ET et al. Genotyping and site-directed mutagenesis of a cytochrome P450 meander Pro-X-Arg motif critical to CYP4B1 catalysis. Toxicol Appl Pharmacol 2003; 186: 119–126.

    Article  CAS  PubMed  Google Scholar 

  32. Rowinsky EK, Noe DA, Ettinger DS, Christian MC, Lubejko BG, Fishman EK et al. Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: hepatotoxicity is dose limiting in humans. Cancer Res 1993; 53: 1794–1801.

    CAS  PubMed  Google Scholar 

  33. Dull T, Zufferey R, Kelly M, Mandel RJ, Nguyen M, Trono D et al. A third-generation lentivirus vector with a conditional packaging system. J Virol 1998; 72: 8463–8471.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Schambach A, Zychlinski D, Ehrnstroem B, Baum C . Biosafety features of lentiviral vectors. Hum Gene Ther 2013; 24: 132–142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Avedillo Diez I, Zychlinski D, Coci EG, Galla M, Modlich U, Dewey RA et al. Development of novel efficient SIN vectors with improved safety features for Wiskott-Aldrich syndrome stem cell based gene therapy. Mol Pharm 2011; 8: 1525–1537.

    PubMed  Google Scholar 

  36. Semple-Rowland SL, Coggin WE, Geesey M, Eccles KS, Abraham L, Pachigar K et al. Expression characteristics of dual-promoter lentiviral vectors targeting retinal photoreceptors and Muller cells. Mol Vis 2010; 16: 916–934.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Szymczak AL, Vignali DA . Development of 2 A peptide-based strategies in the design of multicistronic vectors. Expert Opin Biol Ther 2005; 5: 627–638.

    Article  CAS  PubMed  Google Scholar 

  38. Verrier JD, Madorsky I, Coggin WE, Geesey M, Hochman M, Walling E et al. Bicistronic lentiviruses containing a viral 2 A cleavage sequence reliably co-express two proteins and restore vision to an animal model of LCA1. PLoS ONE 2011; 6: e20553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Yang S, Cohen CJ, Peng PD, Zhao Y, Cassard L, Yu Z et al. Development of optimal bicistronic lentiviral vectors facilitates high-level TCR gene expression and robust tumor cell recognition. Gene Ther 2008; 15: 1411–1423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Donnelly ML, Hughes LE, Luke G, Mendoza H, ten Dam E, Gani D et al. The 'cleavage' activities of foot-and-mouth disease virus 2 A site-directed mutants and naturally occurring '2 A-like' sequences. J Gen Virol 2001; 82: 1027–1041.

    Article  CAS  PubMed  Google Scholar 

  41. Cooper AR, Lill GR, Gschweng EH, Kohn DB . Rescue of splicing-mediated intron loss maximizes expression in lentiviral vectors containing the human ubiquitin C promoter. Nucleic Acids Res 2015; 43: 682–690.

    Article  CAS  PubMed  Google Scholar 

  42. Egerer L, Volk A, Kahle J, Kimpel J, Brauer F, Hermann FG et al. Secreted antiviral entry inhibitory (SAVE) peptides for gene therapy of HIV infection. Mol Ther 2011; 19: 1236–1244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schmidt EM, Wiek C, Parkinson OT, Roellecke K, Freund M, Gombert M et al. Characterization of an Additional Splice Acceptor Site Introduced into CYP4B1 in Hominoidae during Evolution. PLoS ONE 2015; 10: e0137110.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kustikova OS, Wahlers A, Kuhlcke K, Stahle B, Zander AR, Baum C et al. Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population. Blood 2003; 102: 3934–3937.

    Article  CAS  PubMed  Google Scholar 

  45. Lengler J, Holzmuller H, Salmons B, Gunzburg WH, Renner M . FMDV-2 A sequence and protein arrangement contribute to functionality of CYP2B1-reporter fusion protein. Anal Biochem 2005; 343: 116–124.

    Article  CAS  PubMed  Google Scholar 

  46. Rischer M, Pscherer S, Duwe S, Vormoor J, Jurgens H, Rossig C . Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br J Haematol 2004; 126: 583–592.

    Article  CAS  PubMed  Google Scholar 

  47. Roessig C, Scherer SP, Baer A, Vormoor J, Rooney CM, Brenner MK et al. Targeting CD19 with genetically modified EBV-specific human T lymphocytes. Ann Hematol 2002; 81 (Suppl 2): S42–S43.

    CAS  PubMed  Google Scholar 

  48. Fehse B, Richters A, Putimtseva-Scharf K, Klump H, Li Z, Ostertag W et al. CD34 splice variant: an attractive marker for selection of gene-modified cells. Mol Ther 2000; 1: 448–456.

    Article  CAS  PubMed  Google Scholar 

  49. Introna M, Barbui AM, Bambacioni F, Casati C, Gaipa G, Borleri G et al. Genetic modification of human T cells with CD20: a strategy to purify and lyse transduced cells with anti-CD20 antibodies. Hum Gene Ther 2000; 11: 611–620.

    Article  CAS  PubMed  Google Scholar 

  50. Mavilio F, Ferrari G, Rossini S, Nobili N, Bonini C, Casorati G et al. Peripheral blood lymphocytes as target cells of retroviral vector-mediated gene transfer. Blood 1994; 83: 1988–1997.

    CAS  PubMed  Google Scholar 

  51. Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA . Environmental and chemical carcinogenesis. Semin Cancer Biol 2004; 14: 473–486.

    Article  CAS  PubMed  Google Scholar 

  52. Wilson BJ, Garst JE, Linnabary RD, Channell RB . Perilla ketone: a potent lung toxin from the mint plant, Perilla frutescens Britton. Science 1977; 197: 573–574.

    Article  CAS  PubMed  Google Scholar 

  53. Garst JE, Wilson WC, Kristensen NC, Harrison PC, Corbin JE, Simon J et al. Species susceptibility to the pulmonary toxicity of 3-furyl isoamyl ketone (perilla ketone): in vivo support for involvement of the lung monooxygenase system. J Anim Sci 1985; 60: 248–257.

    Article  CAS  PubMed  Google Scholar 

  54. Kerr LA, Johnson BJ, Burrows GE . Intoxication of cattle by Perilla frutescens (purple mint). Vet Hum Toxicol 1986; 28: 412–416.

    CAS  PubMed  Google Scholar 

  55. Frank S, Steffens S, Fischer U, Tlolko A, Rainov NG, Kramm CM . Differential cytotoxicity and bystander effect of the rabbit cytochrome P450 4B1 enzyme gene by two different prodrugs: implications for pharmacogene therapy. Cancer Gene Ther 2002; 9: 178–188.

    Article  CAS  PubMed  Google Scholar 

  56. Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 2014; 124: 1277–1287.

    Article  CAS  PubMed  Google Scholar 

  57. Miller AD . Retroviral Vectors. Curr Top Microbiol Immunol 1992; 158: 1–24.

    CAS  PubMed  Google Scholar 

  58. Lozano G, Martinez-Salas E . Structural insights into viral IRES-dependent translation mechanisms. Curr Opin Virol 2015; 12: 113–120.

    Article  CAS  PubMed  Google Scholar 

  59. Mizuguchi H, Xu Z, Ishii-Watabe A, Uchida E, Hayakawa T . IRES-dependent second gene expression is significantly lower than cap-dependent first gene expression in a bicistronic vector. Mol Ther 2000; 1: 376–382.

    Article  CAS  PubMed  Google Scholar 

  60. de Felipe P, Luke GA, Hughes LE, Gani D, Halpin C, Ryan MD . E unum pluribus: multiple proteins from a self-processing polyprotein. Trends Biotechnol 2006; 24: 68–75.

    Article  CAS  PubMed  Google Scholar 

  61. Szymczak AL, Workman CJ, Wang Y, Vignali KM, Dilioglou S, Vanin EF et al. Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2 A peptide-based retroviral vector. Nat Biotechnol 2004; 22: 589–594.

    Article  CAS  PubMed  Google Scholar 

  62. Arber C, Abhyankar H, Heslop HE, Brenner MK, Liu H, Dotti G et al. The immunogenicity of virus-derived 2 A sequences in immunocompetent individuals. Gene Ther 2013; 20: 958–962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhou X, Dotti G, Krance RA, Martinez CA, Naik S, Kamble RT et al. Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation. Blood 2015; 125: 4103–4113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A et al. Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 2010; 16: 198–204.

    Article  CAS  PubMed  Google Scholar 

  65. Newrzela S, Cornils K, Li Z, Baum C, Brugman MH, Hartmann M et al. Resistance of mature T cells to oncogene transformation. Blood 2008; 112: 2278–2286.

    Article  CAS  PubMed  Google Scholar 

  66. Pastor F, Soldevilla MM, Villanueva H, Kolonias D, Inoges S, de Cerio AL et al. CD28 aptamers as powerful immune response modulators. Mol Ther Nucleic Acids 2013; 2: e98.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Conde J, Ambrosone A, Sanz V, Hernandez Y, Marchesano V, Tian F et al. Design of multifunctional gold nanoparticles for in vitro and in vivo gene silencing. ACS Nano 2012; 6: 8316–8324.

    Article  CAS  PubMed  Google Scholar 

  68. Kennedy LC, Bear AS, Young JK, Lewinski NA, Kim J, Foster AE et al. T cells enhance gold nanoparticle delivery to tumors in vivo. Nanoscale Res Lett 2011; 6: 283.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Matsuura T . Natural furan derivates. Part I. The synthesis of Perilla ketone. Bull Chem Soc Jpn 1957; 30: 430–431.

    Article  CAS  Google Scholar 

  70. Hanenberg H, Xiao XL, Dilloo D, Hashino K, Kato I, Williams DA . Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells. Nat Med 1996; 2: 876–882.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Jörg Schipper, Düsseldorf, Germany, for supporting our research efforts. We would like to express our gratitude to Nadine Lottmann, Stephanie L Kelich and Felicia M Kennedy for expert technical assistance. This work was initially supported by the Deutsche Krebshilfe e. V. (to CMK and HH) and the NIH grant R01 GM49054 (AER). Later support was from the Forschungskommission of the Medical Faculty (39/2012) and the Strategische Forschungsfond of the Heinrich Heine University, Düsseldorf, Germany (to CW), the UW School of Pharmacy Brady Fund for Natural Products Research (to AER), and NIH R01 CA155294 and the Deutsche José-Carreras-Leukämie-Stiftung e. V. DJCLS R 15/10 (Munich, Germany) (to HH). Helmut Hanenberg was supported by the Lilly Foundation Physician/Scientist initiative.

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Author notes

  1. C Wiek and H Hanenberg: These authors equally contributed to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, Düsseldorf, Germany

    K Roellecke, K Scheckenbach, M Wagenmann, C Wiek & H Hanenberg

  2. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    E L Virts

  3. Institute for Organic Chemistry, University of Tübingen, Tübingen, Germany

    R Einholz

  4. Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA, USA

    K Z Edson & A E Rettie

  5. Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany

    B Altvater & C Rossig

  6. Institute for Virology, Innsbruck Medical University, Innsbruck, Austria

    D von Laer

  7. Department of Pediatrics III, University Children’s Hospital Essen, University Duisburg-Essen, Essen, Germany

    D Reinhardt & H Hanenberg

  8. Division of Pediatric Hematology and Oncology, Department of Child and Adolescent Health, University Medical Center Göttingen, Göttingen, Germany

    C M Kramm

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  1. K Roellecke
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Correspondence to C Wiek or H Hanenberg.

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HH may receive royalties based on a license agreement between Indiana University, Indianapolis, IN, USA, and Takara Shuzo Inc., Kyoto, Japan, on the sales and usage of Retronectin® CH296 in transduction protocols. The other authors declare no conflict of interests.

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Roellecke, K., Virts, E., Einholz, R. et al. Optimized human CYP4B1 in combination with the alkylator prodrug 4-ipomeanol serves as a novel suicide gene system for adoptive T-cell therapies. Gene Ther 23, 615–626 (2016). https://doi.org/10.1038/gt.2016.38

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