Cellular Therapies for Treatment of Radiation Injury after a Mass Casualty Incident

In 2004, the Department of Health and Human Services (HHS) tasked the National Institutes of Health (NIH) and specifically, the National Institute of Allergy and Infectious Diseases (NIAID) with the responsibility of identifying and developing medical countermeasures for use in the event of radiological or nuclear incidents. The NIAID’s Radiation and Nuclear Countermeasures Program (RNCP) was established to administer this initiative. A similar mandate from the French Government was enacted with passage of French Order No. 2002-254 of February 22, 2002. This order established the Institut de Radioprotection et de Sûreté Nucléaire (IRSN) as the French Government subject public matter experts in radiation science and its risks. The RNCP funds basic and advanced research on early and delayed injuries that occur after acute radiation exposure. Although recent U.S. licensure of granulocyte growth factors has been achieved, to date, no cellular therapies are approved for the treatment of radiation injuries, in the context of a mass casualty incident. However, the IRSN, with Percy Hospital in France has been at the forefront in the use of these approaches to treat human radiation injuries resulting from accidental exposures. In July, 2015, the NIAID and IRSN co-sponsored a workshop in Paris, France to discuss development of preclinical radiation injury models, strategies using cellular therapies after a mass casualty incident and possible licensure pathways. This commentary provides a brief overview of the data presented at the meeting, and the key points that were discussed; and correspondingly a meeting report (1) that provides a more complete background and discussion of the workshop is available at http://dx.doi.org/10.1667/RR14810.1. Human clinical experience. The first known cellular therapy used to treat radiation exposure was in 1958 at the Curie Institute in Paris, France (2). At that time, a victim from an experimental nuclear reactor accident in Vinca, Yugoslavia was treated with a bone marrow transplant (BMT) after being exposed to radiation. The BMT provided a temporary graft; however, no dramatic change in patient outcome was observed, presumably because the therapy was delivered too late after the incident (first administered at day 28 postirradiation). Following the Chernobyl accident, 13 patients received cell transplants with a 10% survival rate (3). In an evaluation of 58 victims of high doses of radiation (total-body dose .5 Gy), where 29 patients received stem cell transplants; there did not appear to be a significant survival benefit, except in cases where the damage was limited to the hematopoietic system (4). In 1999, following a criticality accident in Tokai-Mura, Japan, two victims who received high-dose exposures (estimated 5.4 Gy of neutrons/8.5 Gy gamma rays for Patient A and 2.9 Gy neutrons/4.5 Gy gamma rays for Patient B) were treated with hematopoietic stem cell transplants (5). The transplants were successful in both patients; however, they later died from multiple organ failure (6). Taking these diverse outcomes into account, a series of meetings and an international consensus conference were convened in 2009, to evaluate the potential use of bone marrow transplants for acute radiation exposures. The final recommendation of the assembled subject matter experts was to administer transplants only in cases where there are no signs of endogenous bone marrow recovery. Further, cytokines should be used as the first line of therapy — based on accidental human exposures where only growth factors were administered and resulted in reasonable success (7). Previous clinical use of cellular therapies for other injuries, including skin, also suggests the potential use of these approaches for treating radiation exposures that do not involve a hematopoietic component. For example, an accident victim in Senegal in 2007 received local mesenchymal stem cell (MSC) injections for cutaneous radiation injury. The treatment, carried out at the same time as surgery to excise the lesion, led to complete healing of 1 Address for correspondence: DAIT, NIAID, NIH 5601 Fishers Lane, Room 7A65; Rockville, MD 20852; email: riosci@niaid.nih. gov.