Radiopharmaceutical therapy in cancer: clinical advances and challenges

Abstract

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.

Fig. 1. Tumour cell irradiation: radiotherapy versus radiopharmaceutical therapy.

a | An external beam delivers the same absorbed dose per cell regardless of the number of cells. b | In radiopharmaceutical therapy, the absorbed dose delivered per cell by emissions originating from cells is influenced by the range of the emissions, the number of cells that are clustered together and the number of cells that have been targeted. A single cell is very difficult to sterilize with radiopharmaceutical therapy. If the range of the emitted particle is much longer than the dimension of the cell nucleus, a smaller fraction of the total emitted energy will be absorbed in the nucleus.

Fig. 2. Publications per year related to RPT.

a | Number of publications related to radiopharmaceutical therapy (RPT) listed in the PubMed database per indicated year for each of the indicated β-particle-emitting radionuclides. The figure shows the introduction and expanded use of new β-particle-emitting radionuclides for RPT. For example, lutetium-177 was first described for use in RPT in 1991 (ref.). By 2018 the number of publications related to lutetium-177 and RPT was about the same as that for yttrium-90. b | Publications per year for RPT with different α-emitting radionuclides. c | Number of publications related to RPT listed in the PubMed database per indicated year for each of the indicated malignancies. See Supplementary information for search terms used. SSR, somatostatin receptor.

Fig. 3. Basic RPT constructs used for radiation delivery.

The various radiopharmaceutical therapy (RPT) constructs that have been used to deliver radiation are illustrated: radioactive element (part a); small molecule (part b); peptide (part c); antibody (part d); nanoconstruct (part e); microsphere (part f).

Fig. 4. PSMA and folate receptor RPT.

a | Prostate-specific membrane antigen (PSMA) inhibitor binding pocket. b | PSMA receptor showing sites of small-molecule and anti-PSMA interactions c | Folate receptor (FR) radiopharmaceutical therapy (RPT). Conjugation of an α-emitter or a β⁻-emitter for therapy or a positron (β⁺)-emitter or a γ-emitter for positron emission tomography or single-photon emission computed tomography, respectively. This is followed by FR targeting. Part a: this research was originally published in JNM. Kopka, K. et al. Glu-ureido–based inhibitors of prostate-specific membrane antigen: lessons learned during the development of a novel class of low-molecular-weight theranostic radiotracers. J. Nucl. Med. 58, 17S–26S (2017), ©SNMMI (ref.). Part b adapted from ref., Springer Nature Limited. Part c, this research was originally published in JNM. Müller, C. et al. Folic acid conjugates for nuclear imaging of folate receptor-positive cancer. J. Nucl. Med. 52, 1–4 (2011), ©SNMMI (ref.).

Fig. 5. Mechanism of action of peptide receptor radionuclide therapy.

The somatostatin analogue (SSA), generally an octreotide derivative, an agonist, is linked to a DOTA chelator, which contains the radionuclide. After binding to the membrane somatostatin receptor (SSR), the radiopeptide is internalized and is transported into the intracellular receptor-recycling compartment. Recently introduced SSR antagonists have overturned this principle, having proven to have significantly lower internalization but greater binding, owing to recruitment of inactive SSRs on the surface of the neuroendocrine tumour cell. Adapted with permission from ref., Elsevier.

Fig. 6. Target antigens that have been used in antibody-based radiopharmaceutical therapy.

Antibodies to a variety of tumour-associated targets may be raised, including leukaemia-associated and lymphoma-associated targets (for example, CD20, CD45 and CD33), targets expressed on solid-tumour cancer cells (for example, carcinoembryonic antigen (CEA), prostate-specific membrane antigen (PSMA) and GD2) and targets expressed on their supporting microenvironment (for example, fibroblast activation protein-α (FAPα)). AML, acute myelogenous leukaemia; APC, antigen-presenting cell; BAFF-R, B cell-activating factor receptor; CAIX, carbonic anhydrase 9; DR, death receptor; sIg, secretory immunoglobulins. Adapted from ref., Springer Nature Limited.