Targeted alpha-particle emitter therapy to fight glioma recurrence
Gliomas are primary brain tumors with a very poor prognosis [1]. About 40% of patients survive the first year after diagnosis, while only 17% of patients survive two years. Due to their infiltrative nature and molecular heterogeneity, the average survival time in this group of patients is 9–15 months, regardless of the comprehensive therapeutic approach, including surgery, radiotherapy and chemotherapy [2]. Despite currently used treatment methods, disease recurrence is observed in 90% of patients within 6 months. There has been no significant improvement in the treatment of this condition in recent decades.
Targeted alpha particle emitter therapy is a relatively new therapeutic method. The high cytotoxic potential (ability to damage cells) of alpha particles combined with appropriate carriers (monoclonal antibodies, peptides or nanoparticles) gives hope for the treatment of even cancers for which classical forms of therapy were not effective.
The Department of Nuclear Medicine UCC WUM (ZMN UCC WUM) has been conducting innovative research for several years on the use of targeted therapy with alpha particle emitters for the treatment of patients diagnosed with recurring glioma.
What is targeted therapy?
The term "targeted therapy" (or "personalized treatment") can be understood as "providing the right patient with the right therapy at the right time". This approach is an alternative to traditional therapeutic procedures, which are based on average treatment effects observed in a typical group of patients. Therefore, it proposes one treatment algorithm for all patients with a given diagnosis.
What is targeted alpha particle emitter therapy?
The method involves administering substance P (neurokinin type 1 receptor ligand, NK-1) labeled with Bi-213 and Ac-225 isotopes directly to the tumor or to the postoperative site (place after tumor resection) [3]. It is based on observations that show that glioma cells (regardless of the degree of malignancy) show significantly increased expression of the NK-1 receptor system. [4]. NK-1 receptors have also been identified in the blood vessel cells of this tumor. This means that gliomas, along with their associated blood vessel network, are characterized by an unusually high number of NK-1 receptors. Thanks to this, we have many potential sites for the selected ligand to bind to cancer cells and their surroundings. The ligand for NK-1 receptors is substance P - a peptide composed of a chain of 10 amino acids (Arg-Pro-Lys-Pro-Gln-Gln-Phe-PheGly-Leu-Met, with amidation at the C-terminus). Due to its low molecular weight (only 1.8 kDa), substance P - after local administration - should freely diffuse within the tumor, combining with glioma cells. Easier diffusion means undisturbed, free spread of the drug in the treated tissue. To sum up, all these features (a large number of NK-1 receptors, easy spread of substance P) provide a chance for the selected substance (radiopharmaceutical) to reach glioma cells, and thus for more effective therapy.
More about alpha particles and their properties in fighting cancer cells
Substance P is labeled with alpha emitters. This alpha radiation is responsible for the therapeutic effect of the entire compound (radiopharmaceutical). Alpha particles are doubly ionized helium nuclei emitted during the decay of radioactive nuclei, usually with an atomic number Z greater than 82. They are more toxic towards cancer target cells than other types of ionizing radiation (e.g. electrons, most often used in radioisotope therapies). Their significant effectiveness is due to their physical properties. They are characterized by a high value of linear energy transfer (LET ≈ 100 keV/µm), so they deposit a lot of energy on a very small section of the path. Moreover, alpha particles have a very small range in matter, < 100 µm, so they penetrate the tissue to a small depth. In practice, this limits their toxic effects mainly to cancer cells. Alpha radiation primarily causes double-stranded damage to the DNA structure. Cell death as a result of this type of damage is largely independent of the oxygenation status and the phase of the cell cycle. All these features ultimately result in delivering a therapeutic dose of alpha radiation only to the target cancer cells, while limiting damage to the surrounding healthy (non-cancerous) tissue.
Among several alpha emitters suitable for use in targeted radioisotope therapy, the isotopes Ac-225 and Bi-213 have proven particularly promising. The chemical properties of trivalent metals Ac(III) and Bi(III) make it possible to obtain a chemically stable connection with substance P using the popular chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid).The chemical stability of radiopharmaceuticals (the combination of an isotope with a ligand via a chelator) is one of the key parameters, because molecules that are highly unstable are not good candidates for effective therapies. The unstable compound would disintegrate before substance P could bind to the NK-1 receptor, and alpha radiation would provide the required amount of energy to selected cancer cells.
Research work on quantitative imaging and calculation of absorbed dose is an introduction to individualized therapy
In phase I and II studies initiated by researchers from ZMN UCK WUM, targeted therapy with substance P labeled with Bi-213/Ac-225 isotopes in patients with recurrent glioblastoma significantly prolongs survival and time to disease progression; compared to other available forms of therapy. The effectiveness and safety of this type of treatment has been the subject of research by scientists representing ZMN UCK WUM for many years. This research activity has been repeatedly appreciated at national and international forums, in the form of scientific awards for the best research in the field of nuclear medicine and neurology.
Further development of the proposed treatment method will depend on the introduction of new radiopharmaceuticals with better biological and chemical properties and methods of their distribution inside the tumor. However, the development of a dosimetric protocol (calculation of the absorbed dose after administration of a selected radiopharmaceutical) will be of particular importance, which will allow linking the therapeutic effect with the absorbed dose delivered.
The first step in calculating the absorbed dose in the case of targeted therapy using substance P labeled with alpha-emitting isotopes is quantitative imaging of the distribution of the radiopharmaceutical in the patient's body. The ZMN UCK WUM team started research on the possibility of imaging the distribution of radiopharmaceuticals labeled with the Ac-225 isotope using the SPECT/CT method at the beginning of 2023, obtaining the first promising results. The hybrid SPECT/CT (single photon emission computed tomography/computed tomography) method is based on the combination of two devices - a gamma camera recording the radiation emitted by the radiopharmaceutical collected in the patient's body and a classic computed tomography scanner. A quantitative imaging protocol was developed to normalize the number of counts in a SPECT/CT image to activity values in Bq units. It will be the basis for further research on calculating the absorbed dose after local administration of substance P labeled with the Ac-225 isotope. It is assumed that the dosimetric approach will allow for further individualization of treatment in this group of patients by determining precisely defined therapeutic activity. Thus, the proposed form of therapy will be tailored to the individual needs of a given patient.
This research direction was also appreciated by the National Science Center in the form of funding in the MINIATURA 7 competition for the scientific activity entitled "Quantitative SPECT/CT imaging and actinium-225 dosimetry for targeted therapy of gliomas using alpha-emitters".
Reference:
[1] Louis D, Perry A, Wesseling P, Brat D, Cree I, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. (2021) 23:1231–51. doi: 10.1093/neuonc/noab106
[2] Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn J, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. (2021) 18:170–86. doi: 10.1038/s41571-020-00447-z
[3] Kunikowska J, Morgenstern A, Pełka K, Bruchertseifer F, Królicki L. Targeted aplpha therapy for gliomlastoma. Front Med (Lausanne). (2022) 9:1085245. doi: 10.3389/fmed.2022.1085245 [4] Hennig I, Laissue J, Horisberger U, Reubi J. Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer. (1995) 61:786–92. doi: 10.1002/ijc.2910610608
[4] Hennig I, Laissue J, Horisberger U, Reubi J. Substance-P receptors in human primary neoplasms: tumoral and vascular localization. Int J Cancer. (1995) 61:786–92. doi: 10.1002/ijc.2910610608
Editor: Communication and Promotion Office
Fot. Michał Teperek; Communication and Promotion Office