Modern cancer therapy has proven partially successful in treating and prolonging the lives of patients with many common types of cancer. This limited success is due in part to the relative lack of specificity seen for many of the primary classes of anticancer agents and cytotoxic technologies in current medical practice. Targeted radionuclide therapy is just one type within the category of “targeted therapies.” At present, effective targeted radiopharmaceutical therapeutics have been developed and validated for a few tumor types, such as malignant lymphoma; for most other tumor types, the older nonspecific types of cancer treatments are still the dominant form of therapy.
A number of critical observations and discoveries have emerged based on previous funding from the National Institutes of Health (NIH) and the Department of Energy (DOE) that have set the stage for advances such as those described below.
Two FDA-approved Labeled Antibodies for the Treatment of Lymphoma Zevalin® and BEXXAR®
are now in general clinical use with impressive response rates and comparatively limited and reversible toxicity. Acknowledged lymphoma experts have noted that the anti-CD20 radioimmunotherapy compounds represent the most active single agents ever developed for the treatment of indolent B-cell lymphoma.
Other Antibodies and Radionuclides in Pre-Clinical and Early Clinical Phases of Testing
Many of these classes of biologically targeted radiopharmaceuticals have shown clear objective responses with acceptable toxicity levels (DeNardo 2005, Sharkey and Goldenberg 2005). These newer classes of therapeutic radiopharmaceuticals include compounds incorporating different antibodies, different radionuclides, and different modes of use. Several groups have recently published results of preclinical and early clinical studies using small molecules or antibodies directed against more common cancers (e.g., lung, breast, colorectal, and brain cancers) and have demonstrated proof of principle. These radioimmunotherapy agents undergoing preclinical and early clinical testing include a variety of radionuclides (with alpha, beta, gamma, and mixed emission spectra), linker chemistries, and half-lives.
Translation of Alpha Particle-Emitting Radiotherapeutics from the Laboratory to the Clinical Setting
Basic chemical advances in labeling molecules at high levels of radioactivity have led to the ability to assess the therapeutic potential of alpha-emitting radionuclides in preclinical models of human malignancy. The predicted localized cytotoxicity of alpha particles has been demonstrated, providing compelling evidence for initiating clinical trials with monoclonal antibodies radiolabeled with an alpha-emitting radionuclide in patients with leukemia and brain tumors.
Therapeutic Benefit in Minimum Residual Disease Settings
Used in an adjuvant (i.e.,postsurgical) setting, the clinical role of radioimmunotherapy would be to eradicate small nests of cells rather than large solid tumors for which much higher doses of radiation would be necessary.
CURRENT STATE OF THE FIELD AND EMERGING PRIORITIES
We are now entering an era of personalized medicine guided by new insights into basic biology and genetics that provide a better understanding of the steps that lead to cancer and other complex diseases. Medical practitioners now realize that tailoring treatment by taking into account an individual’s anatomy, physiology, and genetic background is often required, not only for judicious selection of the drug to be administered but also for determining the appropriate dose of the pharmaceutical. For example, oncologists now are learning to use genetic signatures to determine which breast cancer patients might benefit most from various kinds of cytotoxic chemotherapy and which patients are not good candidates for standard treatments (O’Shaughnessy 2006).Learn More...