Radionuclide therapy of leukemias and multiple myeloma

Monoclonal antibodies (MAbs) raised against cancer antigens may mediate antibody-dependent cell-mediated cytotoxicity. This form of cancer control arises from cytolysis of a target cell by effector lymphocytes, such as cytotoxic T lymphocytes or natural killer cells. However, most of these antibodies have low/moderate efficacy in the tumor control. Antibodies targeting hormone receptors expressed by cancer have shown greater tumor control compared with other cell membrane targets. Moreover, the labeling of these antibodies with a toxin can potentiate their efficacy in the tumor control. In this way, the antibody becomes an invaluable targeting vector for delivery of the toxin to the cancer cells. The toxin/antibody complex is called the immunoconjugate. Different molecules, chemicals, or radioisotopes can serve themselves as toxins; toxins may have long half-lives in the body (e.g., ricin), thus increasing the toxicity to both the cancer and normal tissues. However, the different radioisotopes (e.g., iodine-131, lutetium-177) have a wide range of half-lives and radiation decay that make them useful for different applications. Beta-emitting radioisotopes, predominantly I-131, have had only modest success in radioimmunotherapy. More recently, high linear energy transfer (LET) radiation in the form of alpha particles has been studied: alpha radiation is ideal for killing isolated cancer cells in transit in the vascular and lymphatic systems and regressing tumors by disruption of tumor capillary networks by targeting and killing tumor capillary endothelial cells. Over the past 20 years the development of alpha-immunoconjugates has enabled targeted alpha therapy (TAT) to progress from in vitro studies, through in vivo experiments, to clinical trials. The dose to normal tissues always provides a limitation to the injected dose and that received by the tumor. However, TAT can achieve cancer regression within the maximum tolerance dose for normal tissue. TAT was originally thought to be an ideal therapy for "liquid" cancers, e.g., leukemia and micro-metastases, as the short half-lives of the radioisotopes were sufficient to target these cancer cells and the short range ensured that the targeted cancer cells received the highest radiation dose. Different antibodies have been developed and tested in clinical trials as conditioning treatment, but none of them have yet been approved for radioimmunotherapy (RIT) in multiple myeloma (MM). Addiotinally, bone-seeking radiopharmaceuticals are being evaluated in MM patients in the transplant setting.