Skip to main content

Advertisement

SpringerLink
Log in

Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Introduction

The current systemic anti-metastatic treatment is chemotherapy. Chemotherapy reacts mostly against replicating cells, which makes this therapy not specific. Moreover, resting cancer cells will not be destroyed. A better alternative is an engagement of the host immune system to react against tumor-associated antigens. An efficient immune-stimulating technique is an ablation of the tumor that results in the release of tumor antigens. Our ablation strategy is an innovative alpha-radiation-based technology, diffusing alpha-emitters radiation therapy (DaRT), which efficiently destroys local tumors and provides thereby an antigenic supply for antigen-presenting cells to stimulate T cells.

Methods

Mice bearing weakly immunogenic DA3 adenocarcinoma or highly immunogenic CT26 colon carcinoma were treated by DaRT. Anti-tumor immune responses following tumor destruction were evaluated by (1) the resistance to a tumor challenge; (2) scanning by a CT imaging device for elimination of lung metastases; (3) improved tumor control when combining DaRT with an immunoadjuvant (CpG).

Results

CT26 model: 63–77 % of DaRT-treated mice became resistant to a re-inoculated tumor compared to 29–33 % resistant mice in the control. DA3 model: (1) The growth rate of challenge tumors was the lowest in mice which their primary tumor was treated by DaRT. (2) Most (93 %) mice in the control group developed lung metastases compared to 56 % in the DaRT group. (3) Combining DaRT with CpG resulted in a better control of the primary tumor. Our study offers a technique to eliminate local and distant malignant cells, regardless of their replication status, by stimulating specific anti-tumor immunity through the supply of tumor antigens from the destroyed tumor.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

DaRT:

Diffusing alpha-emitters radiation therapy

DCs:

Dendritic cells

DMBA:

Dimethylbenzanthracene

DMEM:

Dulbecco’s modified Eagle’s medium

HBSS:

Hanks’ balanced salt solution

NNMU:

N-Nitroso-N-methylurethane

ODNs:

Oligodeoxynucleotides

RPMI:

Roswell Park Memorial Institute

References

  1. Weiss EM, Frey B, Rodel F, Herrmann M, Schlucker E, Voll RE, Fietkau R, Gaipl US (2010) Ex vivo– and in vivo–induced dead tumor cells as modulators of antitumor responses. Ann N.Y. Acad Sci 1209:109–117. doi:10.1111/j.1749-6632.2010.05743.x

    Article  CAS  Google Scholar 

  2. Palucka K, Ueno H, Fay J, Banchereau J (2011) Dendritic cells and immunity against cancer. J Intern Med 269:64–73. doi:10.1111/j.1365-2796.2010.02317.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Den Brok MH, Sutmuller RP, van der Voort R, Bennink EJ, Figdor CG, Ruers TJ, Adema GJ (2004) In situ tumor ablation creates an antigen source for the generation of antitumor immunity. Cancer Res 64:4024–4029

    Article  Google Scholar 

  4. Arazi L, Cooks T, Schmidt M, Keisari Y, Kelson I (2007) Treatment of solid tumours by interstitial release of recoiling short-lived alpha emitters. Phys Med Biol 52:5025–5042

    Article  CAS  PubMed  Google Scholar 

  5. Cooks T, Arazi L, Schmidt M, Marshak G, Kelson I, Keisari Y (2008) Growth retardation and destruction of experimental Squamous cell carcinoma by interstitial radioactive wires releasing diffusing alpha-emitting atoms. Int J Cancer 122:1657–1664

    Article  CAS  PubMed  Google Scholar 

  6. Cooks T, Arazi L, Efrati M, Schmidt M, Marshak G, Kelson I, Keisari Y (2009) Interstitial wires releasing diffusing alpha-emitters combined with chemotherapy improved local tumor control and survival in squamous cell carcinoma bearing mice. Cancer 115:1791–1801. doi:10.1002/cncr.24191

    Article  CAS  PubMed  Google Scholar 

  7. Cooks T, Schmidt M, Bittan H, Lazarov E, Arazi L, Kelson I, Keisari Y (2009) Local control of lung derived tumors by diffusing alpha-emitting atoms released from intratumoral wires loaded with Radium-224. Int J Radiat Oncol Biol Phys 74:966–973. doi:10.1016/j.trsl.2011.08.009

    Article  CAS  PubMed  Google Scholar 

  8. Arazi L, Cooks T, Schmidt M, Keisari Y, Kelson I (2010) The treatment of solid tumors by alpha emitters released from 224Ra-loaded sources: internal dosimetry analysis. Phys Med Biol 55:1203–1218. doi:10.1088/0031-9155/55/4/020

    Article  CAS  PubMed  Google Scholar 

  9. Horev-Drori G, Cooks T, Bittan H, Lazarov E, Schmidt M, Arazi L, Efrati M, Kelson I, Keisari Y (2012) Local control of experimental malignant pancreatic tumors by treatment with a combination of chemotherapy and intratumoral 224Radium-loaded wires releasing alpha-emitting atoms. Transl Res 159:32–41. doi:10.1016/j.ijrobp.2009.02.063

    Article  CAS  PubMed  Google Scholar 

  10. Cooks T, Tal M, Raab S, Efrati M, Reitkopf S, Lazarov E, Etzyoni R, Schmidt M, Arazi L, Kelson I, Keisari Y (2012) Intratumoral 224Ra-loaded wires spread alpha-emitters inside solid human tumors in athymic mice achieving tumor control. Anticancer Res 32:5315–5321

    PubMed  Google Scholar 

  11. Coulie PG, Van den Eynde BJ, Van der Bruggen P, Boon T (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14:135–146. doi:10.1038/nrc3670

    Article  CAS  PubMed  Google Scholar 

  12. Aranda F, Llopiz D, Díaz-Valdés N, Riezu-Boj JI, Bezunartea J, Ruiz M, Martínez M, Durantez M, Mansilla C, Prieto J, Lasarte JJ, Borrás-Cuesta F, Sarobe P (2011) Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors. Cancer Res 71:3214–3224. doi:10.1158/0008-5472.CAN-10-3259

    Article  CAS  PubMed  Google Scholar 

  13. Goldstein M, Varghese B, Brody J, Rajapaksa R, Kohrt H, Czerwinski D, Levy S, Levy RA (2011) CpG-loaded tumor cell vaccine induces antitumor CD4 T cells that are effective in adoptive therapy for large and established tumors. Blood 117:118–127. doi:10.1182/blood-2010-06-288456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Nierkens S, den Brok MH, Garcia Z, Togher S, Wagenaars J, Wassink M, Boon L, Ruers TJ, Figdor CG, Schoenberger SP, Adema GJ, Janssen EM (2011) Immune adjuvant efficacy of CpG oligonucleotide in cancer treatment is founded specifically upon TLR9 function in plasmacytoid dendritic cells. Cancer Res 71:6428–6437. doi:10.1158/0008-5472.CAN-11-2154

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Nierkens S, den Brok MH, Sutmuller RP, Grauer OM, Bennink E, Morgan ME, Figdor CG, Ruers TJ, Adema GJ (2008) In vivo colocalization of antigen and CpG within dendritic cells is associated with the efficacy of cancer immunotherapy. Cancer Res 68:5390–5396. doi:10.1158/0008-5472.CAN-07-6023

    Article  CAS  PubMed  Google Scholar 

  16. den Brok MH, Sutmuller RP, Nierkens S, Bennink EJ, Toonen LW, Figdor CG, Ruers TJ, Adema GJ (2006) Synergy between in situ cryoablation and TLR9 stimulation results in a highly effective in vivo dendritic cell vaccine. Cancer Res 66:7285–7292

    Article  Google Scholar 

  17. Yu B, Kusmartsev S, Cheng F, Paolini M, Nefedova Y, Sotomayor E, Gabrilovich D (2003) Effective combination of chemotherapy and dendritic cell administration for the treatment of advanced-stage experimental breast cancer. Clin Cancer Res 9:285–294

    CAS  PubMed  Google Scholar 

  18. Robinson M et al (2009) Novel immunocompetent murine tumor model for evaluation of conditionally replication-competent (oncolytic) murine adenoviral vectors. J Virol 83:3450–3462. doi:10.1128/JVI.02561-08

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Formenti SC, Demaria S (2013) Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst 105:256–265. doi:10.1093/jnci/djs629

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Lindner M, Schirrmacher V (2002) Tumour cell-dendritic cell fusion for cancer immunotherapy: comparison of therapeutic efficiency of polyethylen-glycol versus electro-fusion protocols. Eur J Clin Invest 32:207–217

    Article  PubMed  Google Scholar 

  21. Robinson M, Li B, Ge Y, Ko D, Yendluri S, Harding T, VanRoey M, Spindler KR, Jooss K (2009) Novel immunocompetent murine tumor model for evaluation of conditionally replication –competent (oncolytic) murine adenoviral vectors. J Virol 83:3450–3462. doi:10.1128/JVI.02561-08

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Plotnikov A, Fishman D, Tichler T, Korenstein R, Keisari Y (2004) Low electric field enhanced chemotherapy can cure mice with CT-26 colon carcinoma and induce anti-tumour immunity. Clin Exp Immunol 138:410–416

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Plotnikov A, Tichler T, Korenstein R, Keisari Y (2005) Involvement of the immune response in the cure of metastatic murine CT-26 colon carcinoma by low electric field-enhanced chemotherapy. Int J Cancer 117:816–824

    Article  CAS  PubMed  Google Scholar 

  24. Hodge JW, Guha C, Neefjes J, James L, Gulley (2008) Synergizing radiation therapy and immunotherapy for curing incurable cancers: opportunities and challenges. Oncology 22:1064–1084

    PubMed Central  PubMed  Google Scholar 

  25. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC (2004) Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 58:862–870

    Article  PubMed  Google Scholar 

  26. Jahrsdörfer B, Weiner GJ (2008) CpG oligodeoxynucleotides as immunotherapy in cancer. Update Cancer Ther 3:27–32. doi:10.1016/j.uct.2007.11.003

    Article  PubMed Central  PubMed  Google Scholar 

  27. Sakuishi K, Ngiow SF, Sullivan JM, Teng MW, Kuchroo VK, Smyth MJ, Anderson AC (2013) TIM3 + FOXP3 + regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology 2:1–13

    Article  Google Scholar 

  28. Youn JI, Nagaraj S, Gabrilovich MI (2008) Subset of myeolid: derived suppressor cells in tumor-bearing mice. J Immunol 181:5791–5802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Stap J, Krawczyk PM, Van Oven CH, Barendsen GW, Essers J, Kanaar R, Aten JA (2008) Induction of linear tracks of DNA double-strand breaks by alpha-particle irradiation of cells. Nat Methods 5:261–266. doi:10.1038/nmeth.f.206

    Article  CAS  PubMed  Google Scholar 

  30. Keisari Y (2013) Tumor ablation: effects on systemic and local anti-tumor immunity and on other tumor-microenvironment interactions. Springer, Dordrecht

    Book  Google Scholar 

  31. Gaipl US, Multhoff G, Scheithauer H, Lauber K, Hehlgans S, Frey B, Rödel F (2014) Kill and spread the word: stimulation of antitumor immune responses in the context of radiotherapy. Immunotherapy 6:597–610. doi:10.2217/imt.14.38

    Article  CAS  PubMed  Google Scholar 

  32. Frey B, Rubner Y, Kulzer L, Werthmöller N, Weiss EM, Fietkau R, Gaipl US (2014) Antitumor immune responses induced by ionizing irradiation and further immune stimulation. Cancer Immunol Immunother 63:29–36. doi:10.1007/s00262-013-1474-y

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Gideon Halpern for assistance with the statistical analysis. This work was supported in part by The Roberts-Guthman Chair in Immunopharmacology and The German-Israeli Foundation. This work was performed in partial fulfillment of the requirements toward a PhD degree of Hila Confino, Sackler Faculty of Medicine, Tel Aviv University.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, P.O. Box 39040, Tel Aviv, Israel

    Hila Confino, Ilan Hochman, Margalit Efrati & Yona Keisari

  2. Sackler Faculty of Exact Sciences, School of Physics and Astronomy, Tel Aviv University, Tel Aviv, Israel

    Michael Schmidt & Itzhak Kelson

  3. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Viktor Umansky

  4. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg Mannheim, 69120, Heidelberg, Germany

    Viktor Umansky

Authors
  1. Hila Confino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilan Hochman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margalit Efrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Viktor Umansky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Itzhak Kelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yona Keisari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yona Keisari.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Confino, H., Hochman, I., Efrati, M. et al. Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors. Cancer Immunol Immunother 64, 191–199 (2015). https://doi.org/10.1007/s00262-014-1626-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1626-8

Keywords

Search

Navigation