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Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG

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Abstract

It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG. Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with a MDSC inhibitor (sildenafil), Treg inhibitor (cyclophosphamide at low dose), and the immunostimulant, CpG. Combination of all four therapies led to a complete rejection of primary tumors (in 3 out of 20 tumor-bearing mice) and to the elimination of lung metastases. The treatment with DaRT and Treg or MDSC inhibitors (without CpG) also resulted in a significant reduction in tumor size, reduced the lung metastatic burden, and extended survival compared to the corresponding controls. We suggest that the therapy with DaRT combined with the inhibition of immunosuppressive cells and CpG reinforced both local and systemic anti-tumor immune responses and displayed a significant anti-tumor effect in tumor-bearing mice.

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Abbreviations

Bq:

Becquerel

CP:

Cyclophosphamide

CSC:

Cancer stem cell

CT:

Computed tomography

DaRT:

Diffusing alpha-emitters radiation therapy

i.p:

Intra-peritoneal

i.v:

Intra-venous

MDSC:

Myeloid-derived suppressor cell

NR:

No response

NT:

Non-treated

PBS:

Phosphate buffered saline

PR:

Partial response 

Ra:

Radium

s.c:

Subcutaneous

Treg:

Regulatory T cell

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Acknowledgments

We thank Dr. Gideon Halpern for assistance with the statistical analysis and Kathrin Frank for technical assistance. This work was supported in part by Roberts–Guthman Chair in Immunopharmacology and The German-Israeli Foundation for Scientific Research and Development (GIF) (to Prof. Yona Keisari and Prof. Viktor Umansky). This work was performed in partial fulfillment of the requirements toward a Ph.D. degree of Hila Confino, Sackler Faculty of Medicine, Tel Aviv University.

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Authors and Affiliations

  1. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, P.O.Box 39040, 6997801, Tel Aviv, Israel

    Hila Confino, Margalit Efrati, Ilan Hochman & Yona Keisari

  2. School of Physics and Astronomy, Sackler Faculty of Exact Sciences, 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, Germany

    Viktor Umansky

Authors
  1. Hila Confino
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  2. Michael Schmidt
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  3. Margalit Efrati
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  4. Ilan Hochman
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  5. Viktor Umansky
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  7. Yona Keisari
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Corresponding author

Correspondence to Yona Keisari.

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The authors declare no conflict of interest.

Additional information

Note on previous publications:

1. European Association for Cancer Research (EACR 23), Munich, Germany, July 5–8, 2014. Eur. J. Cancer, 2014, 50, Suppl 5, S213.

2. International Cong. Anti Cancer Res. Sithonia, Greece, Oct. 5–10, 2014. Anti Cancer Res. 2014, 34 (10), 5994–5.

3. Seventh International Conference on Tumor Microenvironment: Progression, Therapy and Prevention, Tel Aviv, Israel, Oct. 11–16, 2015. Cancer Microenvironment, 2015, 8, suppl. 1, S111.

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Confino, H., Schmidt, M., Efrati, M. et al. Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG. Cancer Immunol Immunother 65, 1149–1158 (2016). https://doi.org/10.1007/s00262-016-1878-6

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  • DOI: https://doi.org/10.1007/s00262-016-1878-6

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