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Session Item

Saturday
November 28
16:45 - 17:45
Physics Stream 1
Proffered papers 11: Dose calculation for advanced techniques
Proffered Papers
Physics
11:00 - 11:10
Abolition of metastases of mouse triple negative breast cancer by alpha-radiation and immunotherapy
OC-0083

Abstract

Abolition of metastases of mouse triple negative breast cancer by alpha-radiation and immunotherapy
Authors: Domankevich-Bachar , Vered(1);Efrati , Margalit(1);Mansur , Fairuz(2);Schmidt , Michael(3);Cohen , Adi(2);Glikson , Eran(2);Cooks , Tomer(4);Kelson , Itzhak(3);Keisari , Yona(2)[ykeisari@tauex.tau.ac.il];Galalae, Razvan(5,6)*
(1)Alpha Tau Medical, Basic and Translational Research, Tel Aviv, Israel;(2)Tel-Aviv University / Faculty of Medicine, Clinical Microbiology and Immunology, Tel-Aviv, Israel;(3)Tel Aviv Universit, School of Physics and Astronomy, Tel Aviv, Israel;(4)Ben-Gurion University, Immunology- Microbiology & Genetics, Beer Sheva, Israel;(5)MedAustron, Wiener Neustadt, Austria;(6)Medical Faculty, Christian-Albrechts University, Kiel, Germany;
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Purpose or Objective

Effective treatment of malignant tumors, requires high levels of local control and eradication of metastases. This may be achieved by in situ obliteration of the primary tumor, and release of tumor antigens that trigger systemic immunity. The anti-tumor immunity can be enforced by immuno-adjuvants and inhibitors of immune suppressor cells. In the present study we examined the feasibility to cure mice bearing highly malignant triple negative breast tumors, using integrated alpha radiation and immunotherapy.

Material and Methods

Tumor ablation was performed using Diffusion alpha emitters Radiation Therapy (DaRT). DaRT is an innovative alpha radiation-based treatment for solid tumors applied by intratumoral Ra-224 coated metal seeds, which spread alpha emitting short lived atoms. Tumor ablation by DaRT triggers a systemic and specific antitumor immune response.

Subcutaneous 4T1 tumors (7 mm in diameter) were treated with DaRT seeds (1/tumor, 70 kBq). Poly I:CPEI (polyinosinic:polycitidylic-polyethylene imine; 20 µg/mouse) injected 72 and 24 hours prior to DaRT was used as immunostimulant. Cyclophosphamide (CP) (100 mg/kg; i.p, 1 day before DaRT) was used to inhibit regulatory T cells. Decitabine (1 mg/kg for 4 days before DaRT) was used to de-condense DNA and increase double strand breaks by alpha particles.
Results

Three types of experiments were performed:

I. The effect of DaRT with polyI:CPEI on the development of the primary tumor and on lung metastases was examined. DaRT-polyICPEI treatment significantly attenuated tumor growth during 3 weeks follow up (67±34 mm3) compared with DaRT alone (265±128 mm3) [p(t-test)<0.00005]. Lungs harvested after 4 weeks and imaged for metastases revealed that only 23% in the DaRT+polyICPEI treated mice carried lung metastases compared with 77% in DaRT or 75% in control groups [p (χ2-test) <0.05].

II. Next was tested the effect of DaRT+polyICPEI combined with Tregs inhibition by Cyclophosphamide on lung metastases related mortality under neoadjuvant setting. Residual tumors were resected 14 days after treatment and mice were inspected for 142 days. Most of the DaRT+polyICPEI+CP treated mice (75%) survived, compared with 33% in DaRT, 25% in the Inert (non-radioactive)+polyICPEI +CP, and 12% in the Inert control groups.

III. Finally, DaRT+polyI:CPEI treatment was combined with decitabine. Tumors treated with DaRT+polyI:CPEI+Decitabine, were two-fold smaller compared to the same treatment with non-radioactive seeds (Inert+polyI:CPEI+decitabine), and 4-fold smaller compared to DaRT alone. DaRT+Decitabine retarded tumor development by 64%.
Conclusion

Tumor ablation by DaRT acts as in situ tumor vaccine and by combining it with immunostimulating, Tregs inhibitors and radiosensitizing agents can achieve a higher tumor control, eliminating distant metastases and curing triple negative breast cancer bearing mice. This combination treatment may hold a promise for patients with highly metastatic tumors.