Skip to main content
SpringerLink
Log in

Transarterielle Radioembolisation

Immuneffekte und Immunonkologie

Transarterial radioembolization

Immune effects and immuno-oncology

  • Leitthema
  • Published:
Der Radiologe Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

Die transarterielle Radioembolisation (TARE) stellt ein lokoregionäres, minimal-invasives Therapieverfahren dar, um primäre und sekundäre Lebermalignome zu behandeln.

Ziel

Darstellung des TARE-induzierten immunologischen Effekte und Perspektiven für die Therapieoptimierung mit Immun-Checkpoint-Inhibitoren (ICI).

Ergebnisse

Die Yttrium-90(90Y)-TARE wird bei weitgehend erhaltener Leberfunktion in der Erst- und Zweitlinientherapie bei Cholangio- und hepatozellulären Karzinomen und therapierefraktären Lebermetastasen unterschiedlicher Primarien durchgeführt. Die Kombinationstherapie mit 90Y-TARE und ICI könnte synergistisch die antitumorale Immunität erhöhen und das Outcome verbessern. Aktuell gibt es keine klinischen Studien mit evaluierten immunologischen Daten nach solcher Kombinationstherapie. Zu anderen Isotopen, wie z. B. Holmium-166 (166Ho), fehlen ebenfalls klinische Daten.

Schlussfolgerung

Die klinische Evidenzlage zu ICI in Kombination mit TARE muss deutlich verbessert werden. Dieses alternative Therapiekonzept kann durch das bessere immunologische Verständnis der zellulären Phänotypen, Aktivierung und Funktionen perspektivisch valide, sensitive und spezifische prädiktive Biomarker sowie Modellierung der Patientenauswahl und der entsprechenden optimalen Therapie oder Therapiekombination ermöglichen.

Abstract

Background

Transarterial radioembolization (TARE) is a locoregional minimally invasive therapeutic strategy to treat primary and secondary hepatic neoplasia.

Aim

The objective was to assess TARE-induced immuno-oncological effects and its perspective for potential therapy improvement by using a combinatory strategy with immune checkpoint inhibitors (ICI).

Results

Yttrium-90 (90Y) TARE is used in patients with persisting liver function as the first- and second-line treatment for cholangiocarcinoma and hepatocellular carcinoma and chemotherapy refractory liver metastasis of different primaries. Combination therapy with 90Y TARE and ICI may synergistically improve antitumoral immunity and patient outcome. Currently, there are no clinical studies with published data regarding this combination therapy and the subsequently induced immunological effects. Clinical data on other isotopes, e.g., holmium-166 (166Ho), are also lacking.

Conclusion

The clinical evidence of combined treatment with TARE and ICI must be considerably improved. This innovative therapy concept must be studied in new trials assessing the immunological data, including cellular phenotypes, activation, functions, and biomarkers. This may provide valid, sensitive, and specific models in order to evaluate the optimal therapy concept and/or the therapy combination for the best patient outcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Abbreviations

APZ:

Antigenpräsentierende Zellen

ATP:

Adenosintriphosphat

CD:

Cluster of differentiation

cfDNA:

Circulating free DNA

CRC:

Kolorektales Karzinom

CTLA-4:

Cytotoxic T-lymphocyte-associated protein 4

CyTOF:

Time-of-flight mass cytometry

DAMP:

Damage-associated molecular pattern

DNA:

Desoxyribonukleinsäure

DZ:

Dendritische Zellen

EGFR:

Epidermal growth factor receptor

ESMO:

European Society for Medical Oncology

FOXP3:

Forkhead box P3

GITRL:

Glucocorticoid-induced tumour necrosis factor receptor

Gy:

Gray

GZB:

Granzym B

HCC:

Hepatozelluläres Karzinom

HMGB-1:

High-mobility group protein box 1

HSP70:

Heat shock protein 70

166Ho:

Holmium-166

ICD:

Immunogenic cell death

IFN-γ:

Interferon gamma

MDSC:

Myeloid-derived suppressor cells

MRT:

Magnetresonanztomographie

NGS:

Next Generation Sequencing

NK-Zellen:

Natürliche Killerzellen

NLR:

Neutrophile-Lymphozyten-Ratio

PBMC:

Periphere mononukleäre Blutzellen

PD:

Programmed cell death protein

PDGF:

Platelet-derived growth factor

PD-L:

Programmed cell death 1 ligand

PLR:

Plättchen-Lymphozyten-Ratio

RE:

Radioembolisation

RNA:

Ribonukleinsäure

SIRT:

Selektive intraarterielle Radiotherapie

TACE:

Transarterielle Chemoembolisation

TARE:

Transarterielle Radioembolisation

TIL:

Tumor-infiltrierende Lymphozyten

TME:

Tumour microenvironment

VEGF:

Vascular endothelial growth factor

90Y:

Yttrium-90

Literatur

  1. Ehrhardt GJ, Day DE (1987) Therapeutic use of 90Y microspheres. Int J Rad Appl Instrum B 14:233–242

    Article  CAS  Google Scholar 

  2. Welsh JS, Kennedy AS, Thomadsen B (2006) Selective internal radiation therapy (SIRT) for liver metastases secondary to colorectal adenocarcinoma. Int J Radiat Oncol Biol Phys 66:S62–73

    Article  CAS  Google Scholar 

  3. Salem R, Thurston KG (2006) Radioembolization with 90yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: technical and methodologic considerations. J Vasc Interv Radiol 17:1251–1278

    Article  Google Scholar 

  4. Prompers L, Bucerius J, Brans B, Temur Y, Berger L, Mottaghy FM (2011) Selective internal radiation therapy (SIRT) in primary or secondary liver cancer. Methods 55:253–257

    Article  CAS  Google Scholar 

  5. Klaassen NJM, Arntz MJ, Arranja GA, Roosen J, Nijsen JFW (2019) The various therapeutic applications of the medical isotope holmium-166: a narrative review. EJNMMI Radiopharm Chem 4:19

    Article  Google Scholar 

  6. Sangro B, Martinez-Urbistondo D, Bester L, Bilbao JI, Coldwell DM, Flamen P, Kennedy A, Ricke J, Sharma RA (2017) Prevention and treatment of complications of selective internal radiation therapy: expert guidance and systematic review. Hepatology 66:969–982

    Article  Google Scholar 

  7. Wehrenberg-Klee E, Gandhi RT, Ganguli S (2019) Patient selection and clinical outcomes of Y90 in hepatocellular carcinoma. Tech Vasc Interv Radiol 22:70–73

    Article  Google Scholar 

  8. Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, Nault JC, Neumann U, Ricke J, Sangro B, Schirmacher P, Verslype C, Zech CJ, Arnold D, Martinelli E (2019) Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 30:871–873

    Article  Google Scholar 

  9. Vogel A, Cervantes A, Chau I, Daniele B, Llovet JM, Meyer T, Nault JC, Neumann U, Ricke J, Sangro B, Schirmacher P, Verslype C, Zech CJ, Arnold D, Martinelli E, Committee EG (2018) Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 29:iv238–iv55

    Article  CAS  Google Scholar 

  10. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D’Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Kohne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Osterlund P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taieb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D (2016) ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 27:1386–1422

    Article  CAS  Google Scholar 

  11. Chakedis J, Squires MH, Beal EW, Hughes T, Lewis H, Paredes A, Al-Mansour M, Sun S, Cloyd JM, Pawlik TM (2017) Update on current problems in colorectal liver metastasis. Curr Probl Surg 54:554–602

    Article  Google Scholar 

  12. Weichselbaum RR, Liang H, Deng L, Fu YX (2017) Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol 14:365–379

    Article  CAS  Google Scholar 

  13. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D (2015) The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 41:503–510

    Article  Google Scholar 

  14. Mole RH (1953) Whole body irradiation; radiobiology or medicine? Br J Radiol 26:234–241

    Article  CAS  Google Scholar 

  15. Demaria S, Formenti SC (2020) The abscopal effect 67 years later: from a side story to center stage. Br J Radiol 93:20200042

    Article  Google Scholar 

  16. Hader M, Frey B, Fietkau R, Hecht M, Gaipl US (2020) Immune biological rationales for the design of combined radio- and immunotherapies. Cancer Immunol Immunother 69:293–306

    Article  Google Scholar 

  17. Melucci E, Cosimelli M, Carpanese L, Pizzi G, Izzo F, Fiore F, Golfieri R, Giampalma E, Sperduti I, Ercolani C, Sciuto R, Mancini R, Garufi C, Diodoro MG, Mottolese M, Italian Society of Locoregional Therapies in Oncology (2013) Decrease of survivin, p53 and Bcl‑2 expression in chemorefractory colorectal liver metastases may be predictive of radiosensivity radiosensivity after radioembolization with yttrium-90 resin microspheres. J Exp Clin Cancer Res 32:13

    Article  CAS  Google Scholar 

  18. Schaue D (2017) A century of radiation therapy and adaptive immunity. Front Immunol 8:431

    Article  Google Scholar 

  19. Craciun L, de Wind R, Demetter P, Lucidi V, Bohlok A, Michiels S, Bouazza F, Vouche M, Tancredi I, Verset G, Garaud S, Naveaux C, Galdon MG, Gallo KW, Hendlisz A, Derijckere ID, Flamen P, Larsimont D, Donckier V (2020) Retrospective analysis of the immunogenic effects of intra-arterial locoregional therapies in hepatocellular carcinoma: a rationale for combining selective internal radiation therapy (SIRT) and immunotherapy. BMC Cancer 20:135

    Article  CAS  Google Scholar 

  20. Chew V, Lee YH, Pan L, Nasir NJM, Lim CJ, Chua C, Lai L, Hazirah SN, Lim TKH, Goh BKP, Chung A, Lo RHG, Ng D, Filarca RLF, Albani S, Chow PKH (2019) Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut 68:335–346

    Article  CAS  Google Scholar 

  21. Burnette B, Weichselbaum RR (2015) The immunology of ablative radiation. Semin Radiat Oncol 25:40–45

    Article  Google Scholar 

  22. Chew V, Tow C, Huang C, Bard-Chapeau E, Copeland NG, Jenkins NA, Weber A, Lim KH, Toh HC, Heikenwalder M, Ng IO, Nardin A, Abastado JP (2012) Toll-like receptor 3 expressing tumor parenchyma and infiltrating natural killer cells in hepatocellular carcinoma patients. J Natl Cancer Inst 104:1796–1807

    Article  CAS  Google Scholar 

  23. Charvet C, Canonigo AJ, Becart S, Maurer U, Miletic AV, Swat W, Deckert M, Altman A (2006) Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to FOXO1 and p27kip1 expression. J Immunol 177:5024–5031

    Article  CAS  Google Scholar 

  24. Gerber SA, Sedlacek AL, Cron KR, Murphy SP, Frelinger JG, Lord EM (2013) IFN-gamma mediates the antitumor effects of radiation therapy in a murine colon tumor. Am J Pathol 182:2345–2354

    Article  CAS  Google Scholar 

  25. Sato H, Okonogi N, Nakano T (2020) Rationale of combination of anti-PD-1/PD-L1 antibody therapy and radiotherapy for cancer treatment. Int J Clin Oncol 25(5):801–809. https://doi.org/10.1007/s10147-020-01666-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Domouchtsidou A, Barsegian V, Mueller SP, Best J, Ertle J, Bedreli S, Horn PA, Bockisch A, Lindemann M (2018) Impaired lymphocyte function in patients with hepatic malignancies after selective internal radiotherapy. Cancer Immunol Immunother 67:843–853

    Article  CAS  Google Scholar 

  27. D’Emic N, Engelman A, Molitoris J, Hanlon A, Sharma NK, Moeslein FM, Chuong MD (2016) Prognostic significance of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in patients treated with selective internal radiation therapy. J Gastrointest Oncol 7:269–277

    PubMed  PubMed Central  Google Scholar 

  28. Granier C, Dariane C, Combe P, Verkarre V, Urien S, Badoual C, Roussel H, Mandavit M, Ravel P, Sibony M, Biard L, Radulescu C, Vinatier E, Benhamouda N, Peyromaure M, Oudard S, Mejean A, Timsit MO, Gey A, Tartour E (2017) Tim‑3 expression on tumor-infiltrating PD-1(+)CD8(+) T cells correlates with poor clinical outcome in renal cell carcinoma. Cancer Res 77:1075–1082

    Article  CAS  Google Scholar 

  29. Ricke J, Klumpen HJ, Amthauer H, Bargellini I, Bartenstein P, de Toni EN, Gasbarrini A, Pech M, Peck-Radosavljevic M, Popovic P, Rosmorduc O, Schott E, Seidensticker M, Verslype C, Sangro B, Malfertheiner P (2019) Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma. J Hepatol 71:1164–1174

    Article  CAS  Google Scholar 

  30. Relja B, Land WG (2019) Damage-associated molecular patterns in trauma. Eur J Trauma Emerg Surg. https://doi.org/10.1007/s00068-019-01235-w

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Danksagung

Die Autoren bedanken sich bei Frau A. Janicova für die Anfertigung der Abbildung.

Author information

Authors and Affiliations

  1. Experimentelle Radiologie, Otto-von-Guericke Universität, Leipziger Straße 44, 39120, Magdeburg, Deutschland

    Borna Relja

  2. Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Leipziger Straße 44, 39120, Magdeburg, Deutschland

    Maciej Pech

Authors
  1. Borna Relja
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maciej Pech
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Borna Relja or Maciej Pech.

Ethics declarations

Interessenkonflikt

M. Pech ist user von 166Ho und 90Y. Er hielt Vorträge für und erhielt Studienfinanzierung von SIRTEX. B. Relja gibt an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Relja, B., Pech, M. Transarterielle Radioembolisation. Radiologe 60, 693–703 (2020). https://doi.org/10.1007/s00117-020-00715-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00117-020-00715-0

Schlüsselwörter

Keywords

Search

Navigation