Targeted Alpha Therapy, an Emerging Class of Cancer Agents - A Review

IMPORTANCE: Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types.

OBSERVATIONS: Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle–emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types.

CONCLUSIONS AND RELEVANCE: Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.

ARTICLE INFORMATION Accepted for Publication: May 10, 2018. JAMA Oncol. doi:10.1001/jamaoncol.2018.4044 Published online September 20, 2018.

Targeted Alpha Therapy Working Group Authors: The following investigators take authorship responsibility for the study results: Christopher Parker, MD, FRCR, MRCP; Valerie Lewington, MD; Neal Shore, MD; Clemens Kratochwil, MD; Moshe Levy, MD; Ola Lindén, MD, PhD; Walter Noordzij, MD; Jae Park, MD; Fred Saad, MD. Affiliations of Targeted Alpha Therapy Working Group Authors: The Royal Marsden National Health Service Foundation Trust–Institute of Cancer Research, Sutton, United Kingdom (Parker); King’s College, London, United Kingdom (Lewington); Carolina Urologic Research Center, Myrtle Beach, South Carolina (Shore); University Hospital Heidelberg, Heidelberg, Germany (Kratochwil); Baylor University Medical Center, Dallas, Texas (Levy); Skåne University Hospital, Lund, Sweden (Lindén); Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, the Netherlands (Noordzij); Memorial Sloan Kettering Cancer Center, New York, New York (Park); Centre Hospitalier de l’Université de Montréal, Montréal, Québec, Canada (Saad).

Author Contributions: Dr. Parker had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Parker, Lewington, Shore, Kratochwil, Levy, Lindén, Park, Saad. Acquisition, analysis, or interpretation of data: Parker, Shore, Levy, Noordzij, Park, Saad.
Drafting of the manuscript: Shore, Kratochwil, Lindén, Park, Saad. Critical revision of the manuscript for important intellectual content: Parker, Lewington, Shore, Kratochwil, Levy, Noordzij, Park, Saad.
Statistical analysis: Saad.
Administrative, technical, or material support: Shore, Levy, Noordzij, Saad.
Supervision: Lewington, Shore, Kratochwil, Levy, Lindén, Noordzij, Park, Saad.
Conflict of Interest Disclosures: Dr. Parker reported receiving consulting fees and funding for research activities with Bayer AG and consulting fees from Janssen and AAA Pharmaceutical. Dr. Lewington reported receiving fees for consulting activities with Bayer AG. Dr. Shore reported receiving funding for consulting and research activities with Amgen, Astellas, Bayer AG, Dendreon, Janssen, Pfizer, and Sanofi-Genzyme. Dr. Kratochwil reported receiving funding for consulting activities with Bayer AG. Dr. Noordzij reported receiving fees for consulting activities and nonfinancial support outside of the submitted work from Bayer AG. Dr. Saad reported receiving research funding, fees for consulting activities, and nonfinancial support from Astellas, Bayer AG, and Janssen.
No other disclosures were reported.
Funding/Support: This study was funded by Bayer. Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: Brandon Kent, Ph.D., Chameleon Communications International, provided editorial assistance in the preparation of this manuscript. He was compensated for his contribution.