13/06/2024
Targeted alpha therapy: A promise for effective cancer therapy
By Hudson Alakonya
Cancer, a ferocious healthcare adversary remains one of the most formidable challenges in modern medicine. Despite significant advances in cancer therapies, many cancers are still recalcitrant to conventional treatments such as chemotherapy and radiotherapy. In addition, chemo/radiotherapy results in unwarranted toxicity among patients contributing to unfavorable outcomes. However, amidst this struggle, a new approach of treatment known as Targeted Alpha Therapy (TAT), is offering renewed hope in the efforts to improve treatment efficacy and survival rates. TAT (Figure 1) harnesses the power of alpha radiation, consisting of helium nuclei (alpha particles) emitted by radioactive elements such as Radium-223 and Actinium-225.
The TAT principle is akin to how the atomic bomb works. The nuclear warhead is fitted on a rocket that propels guiding it to a precise location before exploding to cause irreversible damage within a specific radius. Imagine applying this in our bodies to treat cancer! It sounds scary, right? Yes, but this is exactly how TAT is used to bombard cancer cells with high energy radiation killing tumors while sparing normal cells. TAT involves delivering alpha-emitting radionuclides to cancer cells using specific targeting agents, such as monoclonal antibodies, peptides, or small molecules (Figure 2).The targeting vector acts as a rocket designed to bind specifically to cancer cells. When injected into the body, it travels across the body system seeking to accumulate in tumors, sometimes with minimal association with certain tissues. In order for the radiation emitting radionuclide (nuclear warhead) to be delivered to tumors, it has to be attached to the targeting agent through a procedure known as radioconjugation. A molecule known as chelator (e.g DOTA and DTPA) that binds to both the targeting agent such as a monoclonal antibody and the radionuclide such as Actinium-225 is used to link the two. The monoclonal antibody linked to Actinium-225 is then injected into the body traveling across tissues and accumulating in cancer cells. Following delivery, the actinium 225 undergoes a process known as radioactive decay (a spontaneous transformation into a more stable form), emitting high energy alpha particles that act to kill cancer cells (Figure 1).
The main advantage of TAT is the ability to precisely deliver large amounts of energy over a short distance. This is because alpha particles emitting radionuclides travel over short path length (less than 0.01 cm) emitting high linear energy transfer (LET) of approximately 100 keV/μm producing substantially irreparable double strand DNA breaks. The short distance traveled by alpha particles following radioactive decay results in localized energy deposition minimizing collateral damage to surrounding healthy tissue. In addition, the efficacy of TAT is not dependent on oxygen concentration of tissues, making it more effective than external beam radiotherapy or radionuclide therapy using beta/gamma radiation emitting radionuclides. This targeted approach enhances treatment efficacy while improving patient outcomes by reducing the risk of adverse effects associated with traditional cancer treatments.
TAT holds promise as a highly effective form of cancer therapy. Two notable examples of alpha-emitting radionuclides that have demonstrated clinical utility in TAT are Radium 223 and Actinium-225. Radium 223, also known as Xofigo, gained approval for the treatment of metastatic castration-resistant prostate cancer (mCRPC) that metastasize to the bones. This metastatic cancer presents significant challenges due to resistance to standard of care treatments leading to poor outcomes. Radium 223 works by selectively targeting areas of increased bone turnover, such as metastatic lesions, where it emits alpha particles to induce localized cytotoxicity. Clinical trials have demonstrated that treatment with Radium 223 not only improves overall survival but also reduces pain and skeletal-related events in patients with mCRPC. Its targeted mechanism of action and favorable safety profile make Radium 223 a valuable addition to the treatment armamentarium for this challenging disease.
Actinium-225 is another alpha-emitting radionuclide that has shown promise in the clinic, particularly in the treatment of hematologic malignancies such as acute myeloid leukemia (AML) and multiple myeloma. Actinium-225 is typically conjugated with targeting agents, such as monoclonal antibodies or peptides, to specifically deliver radiation to cancer cells expressing surface antigens or receptors. One notable example is the use of Actinium-225 in combination with the CD33-targeting antibody lintuzumab for the treatment of AML. Clinical studies have demonstrated encouraging response rates and durable remissions in patients with relapsed or refractory AML, highlighting the potential of Actinium-225 as a targeted therapy for hematologic malignancies.
Despite its immense promise, TAT is still in the early stages of development and faces several challenges that need to be addressed. These include optimizing targeting strategies, improving radionuclide production and purification methods, and enhancing understanding of the biological effects of alpha radiation on tumor microenvironments. However, ongoing research efforts and technological advancements are rapidly advancing the field of TAT, paving the way for its translation into clinical practice. The clinical success of Radium 223 and Actinium-225 highlights the transformative potential of TAT in addressing the unmet needs of patients with challenging malignancies. As researchers continue to unravel the intricacies of TAT and explore new avenues for innovation, it is poised to play a pivotal role in shaping the future of cancer treatment, bringing us closer to the goal of achieving better outcomes for patients worldwide.
