Diffusing alpha emitters radiation therapy

Diffusing Alpha-emitters Radiation Therapy or DaRT is an alpha-particle-based radiation therapy for the treatment of solid tumors.[1][2]

This therapy was developed at Tel Aviv University in Israel, by Professors Itzhak Kelson and Yona Keisari. The treatment is delivered by the intratumoral insertion of metal tubes called “seeds”, which have Radium-224 atoms fixed to their surface. When the radium decays, its short-lived daughter Radon-220 is released from the seed through recoil energy.[3] The daughters of Radon-220, in particular Pb-212, disperse in the tumor, and emit high-energy alpha particles, which destroy the tumor. Because the alpha-emitting atoms diffuse only a few millimeters in tissue, the DaRT eradicates the tumor cells and spares the surrounding healthy tissue.[3]

Alpha radiation

Alpha radiation is a nuclear phenomenon in which a heavy radionuclide emits an energetic alpha particle (consisting of two protons and two neutrons) and transmutes to a different radionuclide. The emitted alpha particle has a range in tissue of only 40-90 microns, which minimizes collateral damage when used for treatment purposes. However, this also limits its ability to destroy tumors that are many millimeters in diameter. Alpha radiation possesses a potent cell-killing capability because it has a high linear energy transfer (LET) which translates into a high Relative Biological Effectiveness (RBE).[4]

Treatment of cancer

The invention of DaRT makes possible the use of alpha radiation for treating solid tumors, because it overcomes the range limitation of alpha particles in tissue. The daughter atoms of Radium-224 can each diffuse several millimeters in tumor tissue, while emitting alpha particles. The tumor-killing capability of DaRT comes mainly from the ability of alpha radiation to irreparably break the double stranded DNA in tumor cells.[5] This capability does not seem to be dependent on the stage of the cell cycle or the level of oxygenation of the cancer cell.

Preclinical studies in multiple tumor types

Preclinical studies have demonstrated that DaRT can effectively damage all solid tumor types. Studies of 10 different tumor types in mice demonstrated that all responded to DaRT.[6][7][8][9][10][11][12]

Combination therapy of DaRT with either chemotherapy or immunotherapy

In preclinical studies, DaRT effectiveness was enhanced when combined with standard chemotherapies such as 5-FU. In addition, DaRT was able to turn the tumor into its own vaccine and stimulate a systemic anti-tumor immune response.[13] This immune response was effectively augmented by addition of immunostimulants and/or inhibitors of immunosuppressive cells. This immune effect was observed not only as enhanced local tumor destruction at the primary tumor site, but also by elimination of tumor metastases in the lungs.[12][14] These results suggest that DaRT combined with immunotherapy induces a tumor-specific systemic immune response.

Treatment of solid tumors in human patients with DaRT

The first results of the DaRT in human patients, from a pilot study of 28 patients by Prof. Popovtzer (Israel) and Dr. Bellia (Italy), were published in 2020.[15] From among this cohort of elderly patients (median age, 80.5 years), 61% had recurrent and previously treated tumors, including 42% who were radioresistant from prior therapy. Patients were diagnosed with histopathologically confirmed squamous cell carcinoma of the skin or head and neck. One-hundred percent of tumors responded to DaRT, with complete responses occurring in greater than 78% of cases, and no major toxicity was noted. Thirty days after treatment, there was no measurable radioactivity in the blood or urine of patients. Additional studies in larger populations are now ongoing to strengthen support regarding the safety and effectiveness of this technique of intratumoral alpha radiation-based tumor ablation.

References
  1. Arazi, Lior (January 13, 2020). "Diffusing alpha-emitters radiation therapy: approximate modeling of the macroscopic alpha particle dose of a point source". Physics in Medicine & Biology. 65 (1): 015015. Bibcode:2020PMB....65a5015A. doi:10.1088/1361-6560/ab5b73. PMID 31766047. S2CID 208298120.
  2. "Alpha Radiation Emitters Device (DaRT) for the Treatment of Cutaneous, Mucosal or Superficial Soft Tissue Neoplasia. - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2020-07-17.
  3. Arazi, L; Cooks, T; Schmidt, M; Keisari, Y; Kelson, I (2007). "Treatment of solid tumors by interstitial release of recoiling short-lived alpha-emitters". Phys. Med. Biol. 52 (16): 5025–5042. Bibcode:2007PMB....52.5025A. doi:10.1088/0031-9155/52/16/021. PMID 17671351. S2CID 1585204.
  4. Poty, S; Francesconi, L; McDevitt, M; Morris, M; Lewis, J (2018). "α-emitters from radiotherapy from basic radiochemistry to clinical studies - Part 1". J. Nucl. Med. 59 (6): 878–884. doi:10.2967/jnumed.116.186338. PMC 6004557. PMID 29545378.
  5. Seidl, C (2014). "Radioimmunotherapy with α-particle-emitting radionuclides". Immunotherapy. 6 (4): 431–58. doi:10.2217/imt.14.16. PMID 24815783.
  6. 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 (7): 1657–64. doi:10.1002/ijc.23268. PMID 18059026. S2CID 19514265.
  7. 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 (8): 1791–1801. doi:10.1002/cncr.24191. PMID 19197995. S2CID 11018499. Retrieved May 31, 2020.
  8. Cooks, T; Schmidt, M; Bittan, H; Lazorov, 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 (3): 966–73. doi:10.1016/j.ijrobp.2009.02.063. PMID 19480976. Retrieved May 31, 2020.
  9. Cooks, T; Tal, M; Raab, S; Efrati, M; Reitkopf, S; Lazorov, 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 Research. 32 (12): 5315–21. PMID 23225432. Retrieved May 31, 2020.
  10. Horev-Drori, G; Cooks, T; Bittan, H; Lazorov, 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 224 radium-loaded wires releasing alpha-emitting atoms". Transl. Res. 159 (1): 32–41. doi:10.1016/j.trsl.2011.08.009. PMID 22153808. Retrieved June 1, 2020.
  11. Reitkopf-Brodutch, S; Confino, H; Schmidt, M; Cooks, T; Efrati, M; Arazi, L; Rath-Wolfson, L; Marshak, G; Kelson, I; Keisari, Y (2015). "Ablation of experimental colon cancer by intratumoral 224-Radium-loaded wires is mediated by alpha particles released from atoms which spread in the tumor and can be augmented by chemotherapy". Int J Radiat Biol. 91 (2): 179–86. doi:10.3109/09553002.2015.959666. PMID 25179346. S2CID 32999548. Retrieved June 1, 2020.
  12. Confino, H; Schmidt, M; Efrati, M; Hochman, I; Umansky, V; Kelson, I; Keisari, Y (2016). ". Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG". Cancer Immunol Immunother. 65 (10): 1149–58. doi:10.1007/s00262-016-1878-6. PMID 27495172. S2CID 1121535. Retrieved June 2, 2020.
  13. Confino, H; Hochman, I; Efrati, M; Schmidt, M; Umansky, V; Kelson, I; Keisari, Y (2015). "Tumor ablation by intratumoral Ra-224-loaded wires induces anti-tumor immunity against experimental metastatic tumors". Cancer Immunol Immunother. 64 (2): 191–9. doi:10.1007/s00262-014-1626-8. PMID 25326364. S2CID 22025785. Retrieved June 2, 2020.
  14. Domankevich, V; Cohen, A; Efrati, M; Schmidt, M; Rammensee, H; Nair, S; Tewari, A; Kelson, I; Keisari, Y (2019). "Combining alpha radiation-based brachytherapy with immunomodulators promotes complete tumor regression in mice via tumor-specific long-term immune response". Cancer Immunol Immunother. 68 (12): 1949–58. doi:10.1007/s00262-019-02418-5. PMC 6877484. PMID 31637474.
  15. Popovtzer, A; Rosenfeld, E; Mizrachi, A; Bellia, SR; Ben-Hur, R; Feliciani, G; Sarnelli, A; Arazi, L; Deutsch, L; Kelson, I; Keisari, Y (2020). "Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck". Int J Radiat Oncol Biol Phys. 65 (10): 1149–58. doi:10.1016/j.ijrobp.2019.10.048. PMID 31759075.
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