What is Radioimmunotherapy?
Radioimmunotherapy (RIT) is a cancer treatment modality that utilizes monoclonal antibodies (MOABs) chemically linked
to a radioactive atom (radionuclide), and directed against a cancer associated antigen (Ag). For treatment, the RIT drug product is infused, and then binds to the target Ag. Unbound drug is cleared by the kidneys. This results in systemic administration of focused therapeutic radiation to tumor cells, with the potential for sparing normal tissues from the toxic effects of radiation.
History of RIT
Basic research in RIT began in the late 1970's. This was shortly after the discovery of tumor biomarkers, such as PSA, CEA, and AFP which actually are not highly cancer specific. MOABs to these cancer associated antigens were linked to beta emitting radionuclides, such as Iodine 131 and Yttrium 90. Beta radiation from these radionuclide sources has sufficient ionizing energy to kill cancer cells, and path lengths in tissue on the order of 5-1 Omm. Unfortunately, the early clinical trials of RIT against solid tumors did not yield promising results; most likely because the RIT drug was not adequately concentrated in the tumor microenvironment. Consequently, the beta radiation could not achieve significant levels of cancer cell kill without incurring undue toxicity. Zevalin and Bexxar are RIT drugs that utilize a proprietary anti CD20 MOAB moiety that is linked to a beta emitter. They were FDA approved in 2002 and 2003 respectively, as second line treatments for low grade B-Cell Lymphoma. These drugs do have demonstrable clinical activity in this radiation sensitive malignancy. Their clinical utility; however, may have been limited by the fact that this CD20 target Ag target is not cancer specific. Undesirable binding of these drugs to CD20 receptors residing on the surface of normal lymphoid cells within the bone marrow can result in problematic hematologic toxicity from the beta radiation. The RIT products that we have selected for development at Rad Immune utilize MOAB carrier agents that are extremely specific in binding to targets in the tumor microenvironment, and not in normal tissue. This can potentially result in a much more favorable therapeutic index for pharmaceuticals based on our new products. More information about our innovative products, and the basic
research behind their development will be provided on our website in the next few months.
RIT, currently classified by the NCI as a form of Molecular Targeted Radiotherapy (MTR), has recently been experiencing a resurgence in research and development interest. This has been fueled by concomitant advances in immunologic bioengineering, and in tumor biology; as well as by significant basic research progress in the applicable areas of nuclear medicine physics, nuclear chemistry, and radiobiology. One of the most exciting recent advances has been in the area of Alpha Emitting RIT. Alpha emitting radionuclides can be linked to custom MOAB's, and then targeted to highly cancer specific Ag's for a new, potentially more effective approach to RIT. The relative biologic effectiveness (RBE) is the standard measure of cytotoxic potency for therapeutic radiation. Remarkably, alpha rays have an RBE 100 times that of any of the other types of radiation therapy (beta, gamma, Xray photons, and proton beam). Another attractive feature of alpha rays is their extremely short path length in tissue of about 50 microns, or 5 cell diameters. An alpha emitting, cancer specific, targeted drug could therefore offer true micro precision, in terms of normal tissue sparing. By potentially combining very low toxicity with high potency; Alpha emitting RIT holds great promise for future development.
Clinical Advances in Alpha Therapy for Cancer
The recently introduced Bayer Pharmaceutical prostate cancer drug Xofigo (Radium 223) demonstrates the therapeutic potential of targeted alpha emitting systemic radiation treatment. Xofigo is a bone seeking substance that, after concentrating in and around normal osteocytes, can effectively kill prostate cancer cells in adjacent bone metastases. Because of the short path length of the alpha rays, the normal bone marrow cells, located only millimeters away, can be relatively spared from harmful toxicity.
In 2014, the University of Heidelberg Nuclear Medicine Group published a remarkably positive Phase 1 Trial result for their alpha emitting Molecular Targeted Radiotherapy technology in advanced, refractory, metastatic neuroendocrine tumors. Historically, many of the prominent early researchers in the RIT field had hypothesized that alpha emitting therapy could only be effective against micro aggregates or individual cancer cells. This hypothesis was based on the extremely short path length of the alpha rays. Demonstrating that tumor size may not matter - the 2014 Heidelberg study reported that 100% of their patients, all of whom had massive, bulky tumor burdens, exhibited meaningful, long term clinical responses to targeted alpha emitting therapy.