The five “W”s and “How” of Targeted Alpha Therapy: Why? Who? What? Where? When? and How?

Abstract

Cancer is the second cause of death and morbidity in Europe. Unfortunately, currently available treatments cannot permanently cure most cancers, especially when metastatic. New therapy approaches are, therefore, urgently needed. Radionuclide therapy deposits cytotoxic radiation by means of energetic particles (alfa, beta, and auger) labeled to a carrier that specifically targets cancer cells. Targeted Alpha Therapy is very promising, because alpha particles deliver high energy (i.e., cytotoxic effect) in a small range, binding a target cell population without significant harm to healthy tissues. The high linear energy transfer typical of alpha particles determines irreversible double-strand DNA breaks with per-unit absorbed doses of acute biologic effects three-to-seven times greater than the damage produced by external beam with photons or beta radiation. As consequence, cells-not equipped to efficiently repair this type of damage-typically undergo death. Therefore, Targeted Alpha Therapy is such a new approach to treat tumors. This article aimed to provide an overview (five "W"s and "How") on Targeted Alpha Therapy.The author M. Sollini received the international prize "Francesco de Luca" for Cancer Research in 2019, attributed by the Accademia Nazionale dei Lincei, Rome.

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“…Similarly, the efficacy of ED-B chimeric antigen receptor (CAR) T-cell therapy has been recently reported in both in vitro experiments and in animal models [ 47 ]. Further, although β-emitting isotopes still represent the most extensively, clinically used agents, there is growing interest in the use of α-and Auger emitters [ 48 ], which will result in differences in radiobiology and therefore biologically effective doses.…”

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“…Beta particle(β − ) Emission energy per decay: 50-2300 keV Range: 0.05-12 mm Linear Energy Transfer (LET): 0.2 keV/µm Metastatic castration resistant prostate cancer, acute myeloid leukemia, neuroendocrine tumors, acute lymphocytic leukemia, ovarian carcinomas, gliomas, metastatic melanoma, colon cancer, bone metastases [1,3,4] Auger electron (AE)…”

“…Emission energy per decay: 5-9 MeV Range: 40-100 µm LET: 80 keV/µm Metastatic castration resistant prostate cancer, relapsed or refractory CD-22-positive non-Hodgkin lymphoma, acute myeloid leukemia, neuroendocrine tumors, ovarian carcinoma, gliomas, intralesional and systemic melanoma, colon cancer, bone metastases [1,3,4] β − emitting radioisotopes have a relatively long pathlength (≤12 mm) and a lower LET of~0.2 keV/µm, giving them effectiveness in medium-large tumors [1]. However, they lack success in solid cancers with microscopic tumor burden.…”

“…As emissions from radioactive decay, α-particles are naked 4 He nuclei with a +2 charge. They are 7300 times larger than the mass of β − and Auger electrons, giving them significant emission momentum that reduces deflection and results in a near-linear emission path, as opposed to the winding path of β − particles.…”

“…Targeted radionuclide therapy (TRT) is advantageous as it delivers a highly concentrated dose to a tumor site—either directly to the tumor cells or to its microenvironment—while sparing the healthy surrounding tissues. It has been clinically demonstrated using a variety of radionuclides to treat malignancies, including polycythemia, cystic craniopharyngioma, hyperthyroidism, synovitis and arthritis, and numerous cancers, such as thyroid cancer, bone tumors and metastasis, hepatic metastasis, ovarian cancer, neuroendocrine tumors, leukemia, lymphoma, and metastatic prostate cancer [ 2 , 3 , 4 ]. Since radionuclide therapy targets diseases at the cellular level, it has advantages for treating systemic malignancies such as tumor metastases over other forms of therapy such as external beam therapy, where full body irradiation is impossible.…”