Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Our plain-English summary of Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy, by U.B. Hagemann, K. Wickstroem, S. Hammer, et al (Cancer Biotherapy & Radiopharmaceuticals, 2020).

The study

• Authors: U.B. Hagemann, K. Wickstroem, S. Hammer, R.M. Bjerke, S. Zitzmann-Kolbe, O.B. Ryan, J. Karlsson, A. Scholz, H. Hennekes, D. Mumberg, A.S. Cuthbertson
• Journal: Cancer Biotherapy & Radiopharmaceuticals
• Published: 2020;35(7):497-510
• Type of article: Review
• Cited by: 54 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Targeted α therapy (TAT) offers the potential for the targeted delivery of potent α-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (223Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (227Th), the progenitor nuclide of 223Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

In plain English

This article is a review of laboratory and animal research on targeted thorium-227 conjugates (TTCs). In these, thorium-227, a radioactive element that gives off alpha particles, is held by a chelator, a molecule that is in turn attached to antibodies or other targeting molecules. The article does not study asbestos exposure. It covers conjugates aimed at several cancer targets. One of them, MSLN-TTC, targets mesothelin, a protein that earlier studies cited in the review report is found in 80%–95% of mesotheliomas. The review described earlier mouse experiments. In a model using NCI-H226 cells, with 7 animals per group, a single dose of 250 or 500 kBq/kg of MSLN-TTC statistically significantly reduced tumor burden in the lungs and tibia. MSLN-TTC also inhibited tumor growth in tumors where as few as 20% of cells carried mesothelin, and it appeared to be well tolerated in the mice. A phase I trial of MSLN-TTC that includes patients with advanced recurrent epithelioid mesothelioma was recruiting, and no patient results were reported. The authors concluded that TTCs have broad applicability across tumor types. They noted that it remains to be determined whether TTCs can benefit patients with macroscopic tumor burden, and that clinical toxicity studies are still needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of preclinical (laboratory and animal) studies of targeted thorium-227 conjugates, plus a listing of ongoing early clinical trials
• Who was studied: No human study population of the article's own. It reviewed earlier work in human cancer cell lines and mouse xenograft models, including mesothelin-targeted work in several models, and listed ongoing phase I trials.
• Exposure: No asbestos exposure is studied. The agents reviewed are thorium-227 conjugates, in which thorium-227 is held by a chelator attached to antibodies or other targeting molecules. For mesothelioma, the relevant agent is MSLN-TTC, built on the anti-mesothelin antibody anetumab.
• Main results:
  • Citing earlier studies, the review stated that mesothelin expression is highest in mesotheliomas (80%–95%), followed by pancreatic cancer (80%–85%) and ovarian cancers (60%–65%).
  • In a mouse orthotopic bone/lung model using NCI-H226 cells, a single dose of either 250 or 500 kBq/kg of MSLN-TTC statistically significantly reduced tumor burden in the lungs and tibia, with 7 animals per treatment group (results from an earlier study).
  • In a mouse model with mixed mesothelin expression, MSLN-TTC significantly inhibited growth of tumors in which as few as 20% of cells were mesothelin-positive.
  • In all preclinical models tested, MSLN-TTC appeared to be well tolerated in the animals.
  • In mice bearing OVCAR-3 ovarian cancer tumors, MSLN-TTC combined with an ATR inhibitor at doses that were not effective alone showed synergistic activity.
  • A phase I trial of MSLN-TTC (NCT03507452) was recruiting, with an estimated enrollment of 228, in advanced recurrent epithelioid mesothelioma, serous ovarian cancer and, optionally, pancreatic cancer. No results were reported.
• The authors' conclusion: The authors concluded that TTCs have broad applicability across tumor types and that preclinical studies showed activity even in tumors with varying target expression.
• Limitations the authors state:
  • It remains to be determined whether TTCs can be optimized to benefit patients with macroscopic tumor burden.
  • Toxicity of TTCs in patients still has to be investigated in future clinical studies.

Topics

Medical terms in this study, explained in our Lexicon: Glycoprotein, Mesothelin, Mesothelioma, Fibroblast.

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