Current preclinical TAT efforts at the NCI complement the Center for Cancer Research (CCR) Liver Cancer Program, which aims to improve diagnosis and treatment of patients with this disease. Hepatocellular carcinoma (HCC), the most common type of liver cancer, has radiosensitivity comparable to other epithelial tumors and both external and intra-arterially administered radiotherapy represent standard of care treatments for patients with locally advanced HCC . The Laboratory of Molecular Radiotherapy is systematically assessing a range of biomolecule categories (e.g. antibodies and antibody derivatives, peptides, and small molecules) specific to tumor-selective targets for molecular radiotherapy in general and TAT specifically using HCC as a model system [27–29]. Biomolecules are being rigorously screened using in vitro (e.g. target binding in cell-free and isogenic cell-based assays, functionalization, radiolabeling, serum stability) and in vivo studies (e.g. pharmacokinetics, biodistribution, imaging characteristics, and dosimetry) prior to undergoing therapeutic studies (e.g. tumor control, survival, and dosimetry). This approach has the benefit of yielding promising HCC-selective imaging agents, which could be used in identifying recurrent disease after local ablative therapies, which remains a clinical diagnostic challenge. Having access to a platform where diverse biomolecules can be identified, validated, and systematically tested for TAT has the potential to help improve outcomes for patients with HCC. Furthermore, such an approach could be applied to other malignancies as well. Importantly, because these efforts are keenly focused on clinical translation, collaboration with medical, surgical, and radiation oncologists as well as nuclear medicine physicians occurs early in the developmental pipeline.
Much of the work being performed by the Laboratory of Molecular Radiotherapy builds on early foundational work by investigators at NCI. The radiochemistry and pre-clinical studies performed in the NCI Radiation Oncology Branch pioneered the development of chelating agents for radiometals, including alpha-emitters , specifically the CHX-A’’ DTPA that was provided for the first in human clinical trial with 213Bi at Memorial Sloan-Kettering. The chelating agent for 212Pb (203Pb for SPECT imaging), TCMC, was also developed by this group and used in a large number of very large pre-clinical studies treating disseminated peritoneal malignancies to define optimal dose level and response, administration timing, combination strategies with chemotherapeutics, and mechanistic studies of actual in vivo tumor response to all of these therapies. These studies provided the support for the first in human clinical trial with 212Pb at University of Alabama in Birmingham to treat patients with HER2-positive ovarian cancer . Lastly, with all of these truly comparative studies performed, actual per unit dose therapeutic index value of 213Bi, 212Pb, 211At, and 227Th could be determined to optimize the appropriate choice of radionuclide, targeting agent in use in a specific pre-clinical model. These studies clearly established the need to define optimal choices of radionuclide and targeting agent (size and type), as both then apply to the disease presentation in scale and scope. However, while a-emitting radiopharmaceutical research has been an active area of preclinical research by NIH investigators since the 1980’s [32, 33], clinical investigations using TAT did not start at the NIH Clinical Center (CC) until much more recently and benefitted from the boost given to the field by the FDA approval in 2013 of the first clinical α-emitting radiopharmaceutical, 223RaCl2.
Collaborative efforts of diverse groups within the NIH including nuclear medicine, NCI radiochemistry, and other researchers such as Jeffrey Schlom and Thomas Waldmann resulted in important preclinical and clinical work that moved the field of radiopharmaceutical imaging and therapy with b−-emitters using chemistry developed by this same group. Early clinical work in the 1980s by prominent then-NIH intramural investigators such as Steve Larson and Jorge Carrasquillo focused on diagnostic  or primarily β−-emitting therapeutic agents [35, 36], studying issues such as route of administration  and the use of intact versus fragmented antibodies  as ligands for radiopharmaceutical.
While there are many components to NCI’s Intramural Program spread out over many locations, the majority of NCI’s clinical research occurs at the NIH CC located on its main campus in Bethesda, Maryland. The NIH CC opened in 1953 and is one of the only hospitals in the world where the entirety of its operations is focused on clinical research. The CC has 200 inpatient beds and has been a strong proponent of the “bench-to-bedside” model, acting as the clinical testing ground for the many excellent ideas and hypotheses generated from the work of NCI’s intramural preclinical investigators. In 2019, the NIH CC was home to 1,534 active clinical protocols, of which 775 are interventional clinical trials, and recruited over 9,000 new patients with over 95,000 outpatient visits and 42,000 inpatient days to these trials .
For the support of clinical trials related to either diagnostic or therapeutic radiopharmaceuticals, the NIH CC houses in total five β+-emission tomography/computed tomography (PET/CT) scanners, three single-photon emission computerized tomography (SPECT) g-cameras, and two separate locations for radiolabeling compounds for human use including a Good Manufacturing Practice (GMP) radiopharmacy with three medical cyclotrons for PET diagnostic agents. In addition to standard radioactive injection rooms located in several strategic areas throughout the hospital for outpatient radiopharmaceutical administrations, the NIH CC has two shielded hospital suites with staff trained for handling and taking care of radioactive patients. Having an area of the hospital dedicated to radiopharmaceutical treatment such as this allows for more intensive study of radioactive agents and makes possible investigations requiring labor/time-intensive pharmacokinetic or elimination studies, or administration levels high enough to require inpatient stays.
In 2018, the NIH CC administered a dose of a thorium (227Th) TAT to a mesothelioma patient (NCT03507452), becoming the first in the United States to use a human 227Th dose. Currently, there are a number of additional ongoing or planned clinical trials in the NCI Intramural Program using TATs based on 223Ra, 225Ac, and 212Pb in a variety of malignancies including prostate cancer, neuroendocrine tumors, and hepatocellular carcinoma. Furthermore, as is true to the NIH bench-to-bedside paradigm, ongoing pre-clinical work with TAT by NCI investigators will fuel future clinical TAT investigations at the NIH CC [40, 41] .