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Acute radiation syndrome (ARS) results from exposure to high levels of ionizing radiation. This may be the result of an accident, such as exposure of individuals to x-ray diagnostic and therapeutic devices, or a possible large scale exposure following a nuclear facility accident (for example the Chernobyl and Fukushima incidents). It may also be the result of an intentional act of terrorism, involving the use of a radiological dispersal device (i.e., dirty bomb), an improvised nuclear device, or may involve an attack on a nuclear power plant, or any number of potential nuclear scenarios. Following the 9/11 attacks, and more recently the use of non-conventional weapons and toxic industrial compounds in the Syrian civil war and in Iraq by both state and non-state actors, the possibility of intentional exposure to radiation seems to be rising. Since the primary objective of these perpetrators is to create fear and panic to the general public, and since most of the public, as well as first responders, healthcare providers, and the mass media, may have misunderstandings regarding such an event, radiation is attractive. On top of that, the shortage of available medical countermeasures (MCMs) against ARS could make it even worse. The major goals of a response plan to a radio-nuclear emergency are to protect the public, as well as the emergency personnel while performing their duties. To achieve these goals, local, regional and national resources should be brought together to address such an incident of national impact. In a radio-nuclear exposure scenario, the numbers of casualties, some with life-threatening injuries and resulting complications, may be very high. This means major challenges of assessing the precise levels of individual exposure, and possible delayed medical support and care to those who need it. In any case, these are regarded as complex and resource-intensive efforts, driving research towards approving novel MCMs against ARS. This syndrome involves life-threatening injuries especially to the hematopoietic, gastrointestinal, and the neurovascular systems. Victims exposed to high levels of ionized radiation show a prodromal phase in the first few hours following exposure, followed by a latent phase, which shortens as the radiation dose increases, and finally, develop a manifest phase. The bone marrow involvement is considered as the major contributor to mortality.

Though different countries have different approaches and doctrines to handle a radio-nuclear catastrophe, there are several basic assumptions and procedures that cross all nations and organizations. The scope of the response and the resources needed are determined by the extent of the incident, involving local, regional, and national players. Once a radio-nuclear event is recognized, the next step is to notify all relevant organizations, both first responders on site and on the way, as well as governmental departments, crisis management authorities, public health agencies, healthcare facilities and more – depending on the relevant resources allocated for such an incident. A novel protection device that recently reached the markets is the StemRad 360 Gamma wearable shield, which allows the protection of enough bone marrow tissue among first responders and all those who may be exposed to high radiation levels in a way that will ensure their survival. Though these individuals may still be injured and suffer from signs of ARS, this may well save their lives once given the appropriate medical care.

Medical response varies between countries, from field triage, medical condition and contamination assessment, and on site decontamination, to a more scoop-and-run approach, in which contaminated casualties are rushed to the nearest medical facility, where they go through the same process of triage, clinical and contamination assessment, and decontamination at the entrance to the hospital, and then taken inside. The different approaches are driven mainly from evacuation distances, but also from cultural differences between nations. In any case, most of the medical care on site is related to damage control and supportive treatment, and following immediate medical interventions and stabilization efforts as needed, patients are classified based on physical injury, level of exposure, and contamination. The first 36-48 hours following exposure are critical, as this is the time window in which patients with significant exposure will develop hematological and immunological suppression. Laboratory assessment includes complete blood count, cytogenetic tests for chromosomal aberrations, and estimation of internal contamination.

Since there are prodromal and latent phases before the actual clinical deterioration appears, there is a time window allowing for treatment even in a mass casualty scenario.

In general, as medical countermeasures are intended for use in the event of a public health emergency, they must have several characteristics enabling the best response by end-users, including first responders and hospital personnel. These include formulations with high safety profile and efficacy for the desired indications, preferably with no adverse effects, preventing fatalities and reducing morbidity; can be easily delivered to mass casualties in one or more relevant routes of delivery, including IM, intranasal and other delivery modes; and the dosing should be as simple as possible. This is especially important when dealing with a CBRN event, in which the use of personal protective equipment (PPE) by the care givers, with emphasis on masks and gloves, has both physical and mental constraints. MCMs should also account for the needs of special populations including children, and they should be as multifunctional and broad-spectrum as possible. Preferably, they should have long shelf life, with the potential for routine public health applications. Their stability, packaging, storage and transport should help with operational distribution and dispensing efforts to the end-users, ensuring timely, safe and effective utilization. The last component when looking for the appropriate MCM is the price, especially when dealing with mass casualty scenarios that are regarded as possible but rare. In the case of a radio-nuclear event, the ideal MCM drug should be safe for use, without negative effects on non-injured and non-exposed individuals, ameliorate multi-organ failure following different levels of radiation exposure, off the shelf easy-to-use by first responders and medical personnel, and enable the treatment of large numbers of victims.

Pluristem Therapeutics Inc. is a clinical-stage biotherapy company developing placenta-based cell therapy products using a unique three-dimensional technology platform. Pluristem has several products in its pipeline. Each PLacental eXpanded (PLX) cell product displays adaptive responses, releasing a distinct mix of therapeutic proteins (cytokines, chemokines, and others) in response to signals from cells and tissues that have been damaged by conditions such as inflammation, ischemia, hematological disorders, or exposure to radiation. PLX cell products are off-the-shelf, given intramuscularly (IM), requiring no tissue matching prior to administration, making them cost effective and convenient to use in virtually any medical setting.

The U.S. National Institutes of Health (NIH) has supported a series of pre-clinical animal studies conducted under the FDA animal rule with one of Pluristem’s products, PLX-R18, as a novel MCM against ARS. In mouse models, IM injection of PLX‑R18 on days 1 & 5 following ~8 Gy (LD 70:30) total body irradiation resulted in a profound ability to regenerate failing bone marrow and mitigated high dose radiation damage. This was evidenced by almost full survival rate and a faster recovery of weight loss in the treated group vs. a 30% survival rate in the placebo group, with slower weight loss recovery. PLX-R18 treatment demonstrated a significant increase in the number of colony forming progenitors of all three hematopoietic lineages, including platelets, to almost normal values. PLX-R18 cells responded to hematopoietic failure by a transient secretion of a broad spectrum of relevant proteins, including G-CSF, IL-6, MCP-1, MCP-3, and GRO. These reached peak levels several days after the injection and enhanced the reconstitution of the hematopoietic and immune systems. The NIH is now conducting a dose selection study in a large animal model as a final step, in preparation for a pivotal study of PLX-R18 in the treatment of the hematologic component of ARS, to allow marketing approval for ARS.

Pluristem is also targeting additional hematological indications for PLX-R18 and has recently received FDA clearance to initiate a clinical Phase I, open label, dose escalation trial in the treatment of insufficient hematopoietic recovery following hematopoietic cell transplantation. If indeed it will be approved for other indications, it will fulfill another basic MCM demand or advantage, which is a product with routine public health applications.

In the case of PLX-R18 as an MCM against ARS, the decision should be made on where and by who the PLX-R18 will be given. The fact that it is administered IM, given only twice over a period of one week, and does not require any dosage adjustments based on laboratory results, makes the individual exposure assessment unnecessary. This, together with the fact that there is no need for tissue matching, facilitates its use in a radio-nuclear mass casualty scenario. The cold-chain logistics, another important feature of cell-based therapies in general, is achieved by using liquid nitrogen canisters which require no electricity, together with a unique thawing device that enables fast and efficient means to administer the compound safely. Currently-used and stockpiled MCMs against ARS are aimed specifically against one or few of the injured systems. Some have limitations such as side effects or limited time-window for use. Others necessitate monitoring of the effects required. The advantage of PLX-R18 is in the regeneration of all three hematopoietic progenitors, with emphasis on platelets, and so far we have no evidence of any adverse effects. Also, in such a chaotic scenario, it is possible that an unexposed individual will be treated with the compound inadvertently. In this case, we saw PLX-R18 cells responding only when receiving radiation related stress signals, and not responding in unexposed animals. As for other organ systems, initial pre-clinical data demonstrate positive results in the treatment of GI, CNS, and lung injuries, and we are moving forward with our plans for testing the relevance of PLX-R18 as an MCM for other physiological systems, aiming to define it as a broad-spectrum countermeasure. In the future, our goal would be to provide PLX-R18 for both routine and emergency use, with the same handling procedures of the drug by healthcare providers.

So how will PLX-R18 change the way we respond to a radio-nuclear mass casualty event, either accidental or intentional? Following such an incident, the clock starts ticking, with 36-48 hours before victims will start developing ARS. Since there is no need for individual assessment of exposure – except those who are suspected of having internal contamination, people may be directed to hospitals or designated ad-hoc treatment centers to start receiving PLX-R18 based on an environmental risk assessment which can be performed in a relatively short period. Field dosimetry may become less important, though it will still be important at the hospital level. The 36-48 hour time window can allow for a timely distribution of the MCM from its stockpile to the relevant treatment facilities, together with information to both care givers and the public on the compound and the mode of administration. In the case of hospitals located near a nuclear facility, they may keep a stockpile of the compound in advance, as part of their preparedness plan. Since there is no need for tissue matching, no need for dosing adjustments in relation to the level of exposure, and no known adverse effects, the next step following the administration will be to make sure they all come back for the second dose, five days later. Not a simple task, but achievable.

Lt. Colonel Dr. Eisenkraft (Ret.), MD, MHA was formerly Head of Medicine Branch for the Israeli Ministry of Defense where he led pre-clinical & clinical studies and product development for chemical, biological, radiological, and nuclear (CBRN) medical countermeasures.  Prior to that, he was Chief of Chemical Medical Section for the Israeli Defense Forces’ (IDF) Medical Corps where he was leading the development of national medical preparedness doctrines, working closely with governmental agencies, the IDF, and the Israeli Ministry of Health.  Dr. Eisenkraft is now the Director, Homeland Defense Projects. Dr. Eisenkraft will lead development and global commercialization of Pluristem’s cell therapy products for Homeland Security applications.

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