#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Feasibility of real-time in vivo 89Zr-DFO-labeled CAR T-cell trafficking using PET imaging


Autoři: Suk Hyun Lee aff001;  Hyunsu Soh aff003;  Jin Hwa Chung aff003;  Eun Hye Cho aff001;  Sang Ju Lee aff001;  Ji-Min Ju aff005;  Joong Hyuk Sheen aff005;  Hyori Kim aff004;  Seung Jun Oh aff001;  Sang-Jin Lee aff005;  Junho Chung aff006;  Kyungho Choi aff006;  Seog-Young Kim aff004;  Jin-Sook Ryu aff001
Působiště autorů: Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea aff001;  Department of Radiology, Division of Nuclear Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea aff002;  Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea aff003;  Convergence Medicine Research Center, Asan Medical Center, Seoul, Republic of Korea aff004;  Research Institute, National Cancer Center, Gyeonggi-do, Republic of Korea aff005;  Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea aff006
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0223814

Souhrn

Introduction

Chimeric antigen receptor (CAR) T-cells have been recently developed and are producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET).

Results

The 89Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70%–79%, and cell radiolabeling activity was 98.1–103.6 kBq/106 cells. Cell viability after radiolabeling was >95%. Cell proliferation was not significantly different during the early period after radiolabeling, compared with unlabeled cells; however, the proliferative capacity decreased over time (day 7 after labeling). IL-2 or IFN-γ secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance imaging in the xenograft model showed that most of the 89Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by one hour after injection. The cells gradually migrated from the lung to the liver and spleen by day 1, and remained stable in these sites until day 7 (on day 7: lung 3.9% ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89Zr-DFO-labeled hPBMC/CAR T-cells showed a similar distribution, compared with Jurkat/CAR T-cells, on serial PET images. CAR T cell distribution was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry.

Conclusion

Real-time in vivo cell trafficking is feasible using PET imaging of 89Zr-DFO-labeled CAR T-cells. This can be used to investigate cellular kinetics, initial in vivo biodistribution, and safety profiles in future CAR T-cell development.

Klíčová slova:

T cells – Spleen – Polymerase chain reaction – Basic cancer research – Liver – Positron emission tomography – Cancer immunotherapy – Radioactivity


Zdroje

1. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016; 375: 2561–2569. doi: 10.1056/NEJMoa1610497 28029927

2. Curran KJ, Pegram HJ, Brentjens RJ. Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med. 2012; 14: 405–415. doi: 10.1002/jgm.2604 22262649

3. Ho WY, Blattman JN, Dossett ML, Yee C, Greenberg PD. Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell. 2003; 3: 431–437. doi: 10.1016/s1535-6108(03)00113-2 12781360

4. Sadelain M, Riviere I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003; 3: 35–45. doi: 10.1038/nrc971 12509765

5. Kershaw MH, Westwood JA, Darcy PK. Gene-engineered T cells for cancer therapy. Nat Rev Cancer. 2013; 13: 525–541. doi: 10.1038/nrc3565 23880905

6. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013; 5: 177ra138. doi: 10.1126/scitranslmed.3005930 23515080

7. 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. doi: 10.1056/NEJMoa1215134 23527958

8. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011; 3: 95ra73. doi: 10.1126/scitranslmed.3002842 21832238

9. De Oliveira SN, Wang J, Ryan C, Morrison SL, Kohn DB, Hollis RP. A CD19/Fc fusion protein for detection of anti-CD19 chimeric antigen receptors. J Transl Med. 2013; 11: 23. doi: 10.1186/1479-5876-11-23 23360526

10. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016; 6: 664–679. doi: 10.1158/2159-8290.CD-16-0040 27076371

11. Wang H, Du X, Chen WH, Lou J, Xiao HL, Pan YM, et al. Establishment of a quantitative polymerase chain reaction assay for monitoring chimeric antigen receptor T cells in peripheral blood. Transplant Proc. 2018; 50: 104–109. doi: 10.1016/j.transproceed.2017.11.028 29407291

12. Zheng Z, Chinnasamy N, Morgan RA. Protein L: a novel reagent for the detection of chimeric antigen receptor (CAR) expression by flow cytometry. J Transl Med. 2012; 10: 29. doi: 10.1186/1479-5876-10-29 22330761

13. Adonai N, Adonai N, Nguyen KN, Walsh J, Iyer M, Toyokuni T, et al. Ex vivo cell labeling with 64Cu-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for imaging cell trafficking in mice with positron-emission tomography. Proc Natl Acad Sci U S A. 2002; 99: 3030–3035. doi: 10.1073/pnas.052709599 11867752

14. Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, et al. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005; 111: 2198–2202. doi: 10.1161/01.CIR.0000163546.27639.AA 15851598

15. Abou DS, Ku T, Smith-Jones PM. In vivo biodistribution and accumulation of 89Zr in mice. Nucl Med Biol. 2011; 38: 675–681. doi: 10.1016/j.nucmedbio.2010.12.011 21718943

16. Bansal A, Pandey MK, Demirhan YE, Nesbitt JJ, Crespo-Diaz RJ, Terzic A, et al. Novel 89Zr cell labeling approach for PET-based cell trafficking studies. EJNMMI Res. 2015; 5: 19. doi: 10.1186/s13550-015-0098-y 25918673

17. Roca M, de Vries EF, Jamar F, Israel O, Signore A. Guidelines for the labelling of leucocytes with 111In-oxine: inflammation/infection taskgroup of the European association of nuclear medicine. Eur J Nucl Med Mol Imaging. 2010; 37: 835–841. doi: 10.1007/s00259-010-1393-5 20198474

18. Sato N, Wu H, Asiedu KO, Szajek LP, Griffiths GL, Choyke PL. 89Zr-oxine complex PET cell imaging in monitoring cell-based therapies. Radiology. 2015; 275: 490–500. doi: 10.1148/radiol.15142849 25706654

19. Weist MR, Starr R, Aguilar B, Chea J, Miles JK, Poku E, et al. PET of adoptively transferred chimeric antigen receptor T cells with 89Zr-oxine. Journal of Nuclear Medicine. 2018; 59: 1531–1537. doi: 10.2967/jnumed.117.206714 29728514

20. Parente-Pereira AC, Burnet J, Ellison D, Foster J, Davies DM, van der Stegen S, et al. Trafficking of CAR-engineered human T cells following regional or systemic adoptive transfer in SCID beige mice. J Clin Immunol. 2011; 31: 710–718. doi: 10.1007/s10875-011-9532-8 21505816

21. Fisher B, Packard BS, Read EJ, Carrasquillo JA, Carter CS, Topalian SL, et al. Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol. 1989; 7: 250–261. doi: 10.1200/JCO.1989.7.2.250 2644399

22. Pittet MJ, Grimm J, Berger CR, Tamura T, Wojtkiewicz G, Nahrendorf M, et al. In vivo imaging of T cell delivery to tumors after adoptive transfer therapy. Proc Natl Acad Sci U S A. 2007; 104: 12457–12461. doi: 10.1073/pnas.0704460104 17640914

23. Read EJ, Keenan AM, Carter CS, Yolles PS, Davey RJ. In vivo traffic of indium-111-oxine labeled human lymphocytes collected by automated apheresis. J Nucl Med. 1990; 31: 999–1006. 2112185

24. Smith ME, Ford WL. The recirculating lymphocyte pool of the rat: a systematic description of the migratory behaviour of recirculating lymphocytes. Immunology. 1983; 49: 83–94. 6840811

25. Wagstaff J, Gibson C, Thatcher N, Ford WL, Sharma H, Crowther D. Human lymphocyte traffic assessed by indium-111 oxine labelling: clinical observations. Clin Exp Immunol. 1981; 43: 443–449. 7285388

26. Charoenphun P, Meszaros LK, Chuamsaamarkkee K, Sharif-Paghaleh E, Ballinger JR, Ferris TJ, et al. [89Zr]oxinate4 for long-term in vivo cell tracking by positron emission tomography. Eur J Nucl Med Mol Imaging. 2015; 42: 278–287. doi: 10.1007/s00259-014-2945-x 25359636

27. Hamann A, Klugewitz K, Austrup F, Jablonski-Westrich D. Activation induces rapid and profound alterations in the trafficking of T cells. Eur J Immunol. 2000; 30: 3207–3218. doi: 10.1002/1521-4141(200011)30:11<3207::AID-IMMU3207>3.0.CO;2-L 11093136

28. Looney MR, Thornton EE, Sen D, Lamm WJ, Glenny RW, Krummel MF. Stabilized imaging of immune surveillance in the mouse lung. Nat Methods. 2011; 8: 91–96. doi: 10.1038/nmeth.1543 21151136

29. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010; 18: 843–851. doi: 10.1038/mt.2010.24 20179677

30. Chen Y-P, Zhang Y, Lv J-W, Li Y-Q, Wang Y-Q, He Q-M, et al. Genomic analysis of tumor microenvironment immune types across 14 solid cancer types: immunotherapeutic implications. Theranostics. 2017; 7: 3585–3594. doi: 10.7150/thno.21471 28912897

31. Kircher MF, Gambhir SS, Grimm J. Noninvasive cell-tracking methods. Nat Rev Clin Oncol. 2011; 8: 677–688. doi: 10.1038/nrclinonc.2011.141 21946842


Článok vyšiel v časopise

PLOS One


2020 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#