By Ana Ponce Kiess, MD, PhD, and Freddy E. Escorcia, MD, PhD
Promoting Science through Research and Training Subcommittee
In the past six years, we have seen FDA approval of three novel radiopharmaceutical therapies (RPTs): Radium-223 for bone metastases of castrate-resistant prostate cancer, [177Lu]Lu-DOTATATE for neuroendocrine carcinomas, and [131I]I-MIBG for malignant pheochromocytoma and paraganglioma. But with [177Lu]Lu-PSMA agents and many other drugs also in clinical development, are we only seeing the tip of the iceberg?
Paul Wallner, DO, FASTRO, recently provided a timely historical perspective and summary of current clinical uses of radiopharmaceuticals in the spring issue of ASTROnews. While the recent ASTRO Scope of Practice survey shows that only 30% of radiation oncologists currently use RPTs, it is one of the areas of highest interest for expanding scope of practice. At the upcoming ASTRO Annual Meeting in Chicago, a half-day Theranostics Training Workshop on Saturday, September 14, will provide a refresher on relevant physics, pharmacology and radiobiology as well as logistical and practical training in clinical use of radiopharmaceuticals. It will include specific breakout sessions on Ra-223, [177Lu]Lu-DOTATATE, [177Lu]Lu-PSMA agents, [131I]I-MIBG and [90Y]Y-Microspheres, and will also cover important infrastructure, workflow and financial considerations.
Ongoing research in RPTs is even more exciting and demonstrates the depth of the “iceberg” under the surface. There are currently more than 200 clinical trials listed in this category on clinicaltrials.gov. Industry partners are highly committed to the development of RPTs, and academic research has unleashed the potential for combining molecular targeting with the power of radiation to damage DNA and modulate the tumor microenvironment and immune response.
Generally, there are three main pieces of the RPT puzzle: (1) tumor-selective targeting ligands, linked to (2) a chelating group with selectivity for (3) a therapeutic radioisotope. While identifying tumor-specific molecules is very challenging, the advent of next generation sequencing has significantly improved this pursuit, yielding differentially expressed genes in cancers when compared with normal tissue.
Tumor antigen-selective full-length antibodies (~150 KDa) and antibody fragments (25-75 KDa) have been exploited for several decades by pioneers in the field, ultimately resulting in FDA approvals. Newer methods to engineer diverse proteins and peptides of varying sizes with selectivity to virtually any target of interest has resulted in a myriad of molecules that could be used as ligands for RPT agents. Unsurprisingly, the size of these molecules plays a critical role in both the pharmacokinetics of the drug as well as the penetration of solid tumors, and the agents that have received the most interest are peptide (e.g., DOTATATE) or small molecule (e.g., PSMA targeting ligands) based. Engineered antibodies such as minibodies (~75 KDa), single-chain variable fragments (scFvs, ~25 KDa) and single domain antibodies (~15 KDa) have also demonstrated promise as tumor specific ligands for radiopharmaceutical-based imaging and therapy.1-3 Other molecules such as Affibodies and DARPins have also been explored with varying levels of success.
The diversity and quality of radioisotopes available for preclinical and clinical use has also improved. The Department of Energy has made significant commitments toward ensuring that this critical resource is available for domestic development. Investigators typically select the radioisotope physical half-life to match the blood half-life of the scaffold to which it is coupled. One notable feature that has been exploited is the pairing of a diagnostic imaging molecule that can highlight tumor distribution in vivo prior to administration of the therapeutic partner (e.g., same scaffold, different radioisotope). For example, [68Ga]Ga-DOTATATE is the imaging partner to the therapeutic [177Lu]Lu-DOTATATE.
The type of radioactive emission (e.g., beta, alpha) of a given radionuclide is also important and expected to have different therapeutic and safety considerations. The high linear energy transfer (LET) and short path length (a few cell diameters) of alpha-particles, for instance, confers significant potential for tumor cell kill with sparing of surrounding tissue if targeted specifically to tumors. Theory has become reality as specific cases of Ac-225 coupled to PSMA-targeting ligands have resulted in not only radiographic, but also biochemical complete responses, even in patients who were refractory to the same ligand coupled with Lu-177.4-5 However, there is also evidence of increased side effects compared to beta emitters, such as dose-limiting xerostomia with [225Ac]Ac-PSMA agents.6 Recent reports of Pb-212, another alpha-emitter, conjugated to octreotate (the molecule from which DOTATATE is derived) in patients have demonstrated tolerability.
Importantly, significant work remains to be done in standardizing absorbed dose estimates of systemically administered RPTs, accounting for not only radioisotope and ligand particularities, but also heterogeneity in tumor burden across patient populations. Furthermore, systematic assessments of normal organ dose and function in the setting of therapeutic doses of radioisotopes are needed to rival those we use daily for external beam constraints for organs at risk.
As Dr. Wallner highlighted, this is one of several waves of interest in RPTs over the years. However, this generation of emerging RPTs is likely to continue expanding in the context of advances in identifying tumor-selective markers, ligand generation and radioisotope availability. Radiation oncologists, in partnership with our colleagues in nuclear medicine and medical oncology, are poised to deliver the promise of these new agents safely and effectively to our patients.
Do you use radiopharmaceutical therapies in your practice? Please share your experiences in the comments below.
Learn more about the Theranostics Workshop, taking place on Saturday, September 14, at the ASTRO Annual Meeting in Chicago.
Dr. Ana Kiess is assistant professor and residency program director in the Department of Radiation Oncology at Johns Hopkins University. Dr. Freddy Escorcia is an assistant clinical investigator within the Molecular Imaging Program and the Radiation Oncology Branch at the NCI Center for Cancer Research where he heads the Laboratory of Molecular Radiotherapy.
- Pandit-Taskar N, O'Donoghue JA, Ruan S, Lyashchenko SK, Carrasquillo JA, Heller G, et al. First-in-Human Imaging with 89Zr-Df-IAB2M Anti-PSMA Minibody in Patients with Metastatic Prostate Cancer: Pharmacokinetics, Biodistribution, Dosimetry, and Lesion Uptake. J Nucl Med. 2016;57:1858-64.
- Zettlitz KA, Tavare R, Tsai WK, Yamada RE, Ha NS, Collins J, et al. (18)F-labeled anti-human CD20 cys-diabody for same-day immunoPET in a model of aggressive B cell lymphoma in human CD20 transgenic mice. Eur J Nucl Med Mol Imaging. 2019;46:489-500.
- Rashidian M, Ingram JR, Dougan M, Dongre A, Whang KA, LeGall C, et al. Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med. 2017;214:2243-55.
- Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-Targeted alpha-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2016;57:1941-4.
- Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. (225)Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46:129-38.
- Kratochwil et al. 225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2016;57(12):1941-44.