Sargramostim in acute radiation syndrome

ABSTRACT

Introduction

Since 1944, nearly 400 radiologic accidents/incidents have exposed about 3,000 people to substantial doses of ionizing radiation, with more than 125 deaths. Known are the Chernobyl and Fukushima nuclear power facility accidents, but the recent war in Ukraine has refocused attention on this issue. Therapy of acute, high-dose, whole-body exposures to ionizing radiation includes transfusions, antimicrobial drugs, molecularly cloned hematopoietic growth factors, and hematopoietic cell transplants (HCT).

Areas covered

We focus on approved therapies including recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim). Animal data indicate sargramostim accelerates marrow recovery and increases survival. In 2018, the United States Food and Drug Administration approved sargramostim for persons acutely exposed to myelosuppressive radiation doses based on two large nonhuman primate studies. In seven radiation accidents since 1986, 28 victims exposed to acute high-dose ionizing radiation received rhu GM-CSF alone or with other hematopoietic growth factors. Therapy appeared effective with few, if any, adverse events; 18 survived.

Expert opinion

This favorable benefit-to-risk ratio suggests giving sargramostim soon after exposure and is favored over HCT based on greater safety and fewer resource requirements, especially in the context of large-scale exposures which might occur after use of a tactical nuclear weapon or nuclear terrorism.

KEYWORDS:

• Acute radiation syndrome
• colony-stimulating factor
• filgrastim
• G-CSF
• myeloid growth factors
• radiation and nuclear countermeasures
• recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)
• sargramostim

1. Introduction

Humans exposed to acute, high-dose, and high-dose-rate, whole-body ionizing radiation such as after a radiation or nuclear accident develop hematopoietic acute radiation syndrome (H-ARS) characterized by acute, severe myelosuppression with resultant infection, bleeding, and anemia. Such accidental exposures are rare, and it is unlikely most physicians will encounter someone with H-ARS. However, the threat of a radiation or nuclear incident is increasing because of the risk of nuclear terrorism and wars in countries with nuclear power facilities such as Ukraine [1–6]. Moreover, the US Government General Accounting Office (GAO) reports there are about 10 million ‘sealed sources’ of radioactive devices in the US [7]. These devices are used for medical, industrial, agricultural, and research purposes and often contain ¹³⁷Cs or ⁶⁰Co. Since 1995, more than 600 devices have been lost or stolen with less than one-half recovered [7–9]. These unrecovered radioactive devices present a substantial threat to national security if stolen by terrorists and then dispersed in populated areas [6].

There have been nearly 400 radiologic accidents since 1944 exposing about 3,000 people to substantial doses of ionizing radiation with more than 125 deaths. The most widely known are the Chernobyl and Fukushima nuclear power facility accidents but the recent war in Ukraine has refocused attention on this issue. Therapy of acute, high-dose, and high-dose-rate, whole-body exposures to ionizing radiation is complex and requires accurate dose, dose-rate, source-term parameters (the amount of radionuclides released into the environment over a specified interval), and field uniformity estimates based on physical, biological, and simulation measurements [10–12]. Unfortunately, these data and estimates are often unavailable or have wide confidence intervals. Potential interventions include vigorous supportive care, red blood cell and platelet transfusions, preventative or therapeutic antimicrobial drugs, molecularly cloned hematopoietic growth factors, and hematopoietic cell transplants (HCT). Although we note and briefly comment upon unapproved products, we address those agents that have been US Food and Drug Administration (US FDA)-approved, compare them, and comment on treatment gaps. We adhere to the theme of products approved by the US FDA under the Animal Rule and examine the nonclinical (nonhuman primate) data resulting in their approval. We focus on the historical use of recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim, Leukine, Partner Therapeutics, Lexington, MA) to treat acute, high-dose, and high-dose-rate ionizing radiation exposures.

2. Background

Effects of exposure to acute, whole-body radiation doses are correlated with dose, dose-rate, field, and source-term parameters [6,13,14]. Exposures above 1–2 Gy cause substantial, adverse effects [15]. Doses greater than 2 Gy are associated with H-ARS. Doses 6–8 Gy or higher cause gastrointestinal damage termed gastrointestinal tract-acute radiation syndrome (GI-ARS). In accident settings, there are often overlapping injuries from physical (percussive) forces, chemical and thermal vectors which cause multi-system organ failure [16–18].

Persons exposed to doses less than 2 Gy at dose rates less than 5 cGy/min need monitoring but not medical interventions. Doses above 10 Gy at high-dose-rates are rapidly fatal where cardiovascular, central nervous system, and other fatal organ damage may predominate. Because of these considerations, we focus on interventions in persons exposed to doses of 2–10 Gy (H-ARS) and where medical interventions may save lives.

3. Interventions

Several drugs have been evaluated for use as medical countermeasures to H-ARS including amifostine, palifermin (keratinocyte growth factor), recombinant erythropoietin products, interleukin-3, interleukin-11 (oprelvekin), romiplostim (Nplate, approved by the FDA in 2021 to treat thrombocytopenia/H-ARS based on nonhuman primate data), and placenta-derived ex vivo expanded cells PLX-R18 (Pluristem Therapeutics, Haifa, Israel) [4,9,19,20]. While there are some preclinical and some basic safety data in humans, none of these drugs, with the exception of romiplostim, are US FDA-approved in the setting of H-ARS. Our focus is on the use of molecularly cloned hematopoietic growth factors, especially sargramostim.

3.1. Molecularly cloned myeloid growth factors

Three molecularly cloned hematopoietic growth factors are US FDA-approved to increase survival in adult and pediatric patients acutely exposed to myelosuppressive doses of radiation (hematopoietic syndrome of acute radiation syndrome, or ‘H-ARS’ [21–23]) and accelerate bone marrow recovery after exposure to acute, high-dose, and high-dose-rate ionizing radiation in accidents and other settings. These include recombinant human granulocyte colony-stimulating factor (rhu G-CSF, filgrastim, Neupogen™; Amgen, Thousand Oaks, CA); pegylated rh G-CSF (pegylated filgrastim, Neulasta™, Amgen); and recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim, Leukine, Partner Therapeutics, Lexington, MA) [21–25]. We will not discuss other forms of GM-CSF myeloid growth factors such as regramostim or molgramostim, which are unstudied in this H-ARS setting and are not approved by the US FDA for use in any indication.

3.2. G-CSF and GM-CSF

Moleculary cloned hematopoietic growth factors have been used for more than 30 years in diverse clinical settings to accelerate bone marrow recovery [26,27]. G-CSF is a lineage-specific, colony-stimulating factor produced by monocytes, fibroblasts, and endothelial cells. G-CSF increases production, differentiation, and activation of granulocytes which results in increased phagocytosis, antibody-directed cell cytotoxicity (ADCC) and increases cell surface antigen expression [28]. The US FDA has approved G-CSF to (1) accelerate bone marrow recovery after exposure to bone marrow suppressing drugs and/or ionizing radiation; (2) facilitate mobilization of blood cells for HCT; and (3) treat subjects with severe, chronic neutropenia.

GM-CSF acts on a much wider range of cells compared with G-CSF including granulocytes, myeloid-derived dendritic cells, megakaryocytes, and erythroid progenitors [29–32]. Sargramostim supports proliferation, differentiation, maturation, and survival of cells of several myeloid lineages. It also activates mature granulocytes and macrophages. The US FDA has approved sargramostim (rhu GM-CSF) to (1) accelerate bone marrow recovery after treatment with bone marrow suppressing drugs and/or ionizing radiation; (2) mobilize blood cells for HCT; and (3) treat post-HCT graft-failure. Giving sargramostim to persons exposed to high-dose radiation within 2 days is reasonable in accident settings of minimal supportive care as might happen after a large-scale radiation or nuclear incident [33]. In fact, Zhong et al. [34] used the nonhuman primate model to evaluate the efficacy of daily subcutaneous dosing of sargramostim with total body irradiation (TBI) regimens delivered at 48, 72, 96, or 120 h after radiation exposure. Delayed sargramostim treatment at 48 h post-irradiation significantly reduced mortality (p = .0032) and improved neutrophil as well as lymphocyte and platelet counts. Additional delays in sargramostim administration at 72, 96, and 120 h after irradiation were also similarly effective at enhancing the recovery of lymphocyte, neutrophil, and platelet counts when compared to control. Sargramostim treatment also improved the survival of the animals when administered at up to 96 h post-irradiation. The US FDA approval was based upon the nonhuman primate TBI model data described by Clayton and associates [35] and by Doyle-Eisele [36]. The FDA concluded in its Multi-Disciplinary Review and Evaluation that:

Leukine provides patients exposed to myelosuppressive doses of radiation a treatment option shown to be effective in increasing survival with a delay in start of treatment up to 48 hours and in the setting of minimal supportive care that mimics the limited resource environment in a radionuclear mass casualty event. [33]

4. Preclinical data in nonhuman primates

Table 1 shows data regarding acceleration of bone marrow recovery for US FDA clinically approved agents based upon non-clinical data from nonhuman primates [33–43]. Efficacy and safety of sargramostim as a therapy for H-ARS is based on animal efficacy studies under the Animal Rule and on evidence of sargramostim for use in other approved indications [44]. Initial evidence of efficacy was based upon a randomized, double-blinded, vehicle-controlled study conducted under Good Laboratory Practice [33]. For example, Clayton and colleagues evaluated the efficacy of sargramostim (7 µg/kg/day) compared with control for 60-day survival in male and female rhesus macaques receiving whole-body ionizing radiation at a 50–60% lethal dose (LD_50-60) [35]. Sargramostim was started 48 h post-irradiation and only minimal supportive care was given, the latter specifically including antibiotics and anti-emetics in prophylactic fashion, fluids, anti-ulceratives, and analgesics as needed, but no blood, plasma or platelet transfusions. Granulocyte, platelet, reticulocyte, and lymphocyte recoveries were accelerated and the incidence of sepsis, hemorrhage and infections were decreased. Sixty-day survival increased to 78% (95% confidence interval, 61, 90%) compared with 42% (26, 59%; p = 0.002) in controls. A similar treatment effect was also observed at the LD_70-80 dose. Although these data are encouraging, this model may differ from what is likely in the context of a radiation accident where there are expected to be concomitant injuries and where exposed persons may have comorbidities. Also, radiation dose, dose-rate, field, and source-term parameters (the amount of radionuclides released into the environment over a specified interval) are known.

Table 1. Summary of data on efficacy of FDA-approved medical countermeasures for TBI H-ARS in nonhuman primates [33–43].

	Sargramostim (Leukine)	Filgrastim (Neupogen)	Pegylated filgrastim (Neulasta)	Romiplastim (Nplate)
Effective without Blood Transfusions	Yes	No	No	Yes
Reduces Infection	Yes	Yes	Yes	No
Reduces Hemorrhage	Yes	No	No	Yes
Improves Anemia	Yes	No	No	No
Accelerates Lymphocyte Recovery	Yes	No	No	No
Accelerates Monocyte Recovery	Yes	No	No	No
Accelerates Neutrophil Recovery	Yes	Yes	Yes	No
Accelerates Eosinophil Recovery	Yes	No	No	No
Accelerates Platelet Recovery	Yes	No	No	Yes
Accelerates Erythrocyte/Reticulocyte Recovery	Yes	No	No	No
Treatment Effective When Administered up to	96 h	24 h	24 h	24 h

5. Radiation accidents and incidents

We and others reviewed publications on the use of molecularly cloned myeloid growth factors in radiation accidents [10–13,45–47]. For several reasons, it is difficult to evaluate safety and efficacy of this approach. First, few subjects were treated. Second, radiation doses and field uniformity are typically imprecise estimates. Third, the interval from exposure to starting therapy varied considerably. Fourth, other interventions were often given synchronously or metachronously. The greatest obstacle is lack of a control cohort.

5.1. US Strategic National Stockpile

The US Strategic National Stockpile (SNS) is a national repository of antibiotics, chemical antidotes, antitoxins, life support medications, airway maintenance supplies, and medical/surgical items (https://www.phe.gov/about/sns) [47–50]. Products believed to be held for use during a potential nuclear incident include

• FDA-approved H-ARS medical countermeasures including sargramostim, pegylated filgrastim, filgrastim, and romiplastim

• Anti-nausea and analgesic medications

• Antibiotics, antivirals, and antifungals

• Decorporation agents for internal contamination including isotopic dilution agents, diuretics, adsorbents, and chelating agents.

5.2. Accidents where GM-CSF was given

Table 2 displays data from seven accidents where rhu GM-CSF was given. These accidents occurred from 1986 (Chernobyl, Ukraine) to 2000 (Thailand) involving 28 persons who received rhu GM-CSF alone or with other hematopoietic growth factors [51–63]. Four accidents involved a ⁶⁰Co source. Exposures were acute or protracted and the dose of rhu GM-CSF was like that used clinically. Ten recipients died, nine at 1–3 months after exposure. The four deaths in the Goiania accident were in persons with bacterial infections before receiving rhu GM-CSF. Eighteen recipients survived, but long-term outcomes for most are unknown.

Table 2. Radiologic accidents where victims received rhu GM-CSF [50–62].

Refs	Accident site & year	Radiation source	Exposure and dose	No. victims treated	rhu GM-CSF dose	Outcomes
[50–52]	Chernobyl, Ukraine 1986	Numerous radionucleides	Acute 5 Gy	3	No details available	1 Death on day 2 2 Survived
[53,54]	Goiania, Brazil 1987	^137Cesium	Protracted 2.5–6.0 Gy	8	500 µg/m^2/d	4 Deaths (all had bacterial infections at time rhu GM-CSF begun) 4 Survived
[55,56]	San Salvador, El Salvador 1989	^60Cobalt	Acute 3.0–8.2 Gy	3	240 µg/m^2/d	1 Death 2 Survived
[57]	Nesvizh, Belarus 1992	^60Cobalt	Acute 11–15 Gy	1	6–11.4 µg/kg/day^a	Death day 108 (pneumonia & ARF)
[58]	Henan Province, China 1999	^60Cobalt	Protracted 2.5–6.1 Gy	3	200–400 µg/m^2/day^b	3 Survived
[53,59,60]	Vanango, Peru 1999	^192Iridium	Protracted 80–143 Gy	1	300 µg/day^c	Survived
[61,62]	Samut Prakan, Thailand 2000	^60Cobalt	Acute & protracted 1 – > 6 Gy	9	300–600 µg/day^c	3 Deaths days 38, 47, 53 6 Survived

^aIL-3 also given; ^brecombinant erythropoietin also given; ^cG-CSF also given. ARF, acute respiratory failure; GvHD, graft-versus-host disease.

Used with permission of Society for Radiological Protection, from [45]; permission conveyed through Copyright Clearance Center, Inc.

5.3. Accidents where a subsequent HCT was done

Five of the accident victims in the above analysis were excluded because of confounding subsequent HCT. Three victims in a 1999 accident in a uranium reprocessing plant in Tokaimura, Japan, received G-CSF followed by a HCT but died of multi-organ failure [64–66]. One victim of a 2008 radiation accident in Taiyuan, China, received G-CSF followed by HCT and a mesenchymal stromal cells infusion [67]. He died of multiorgan failure. One victim of a 1990 radiation accident in Soreq, Israel, received rhu GM-CSF and an HCT but died from graft-versus-host disease (GvHD) [68].

6. Key areas for improvement

Appropriate use of interventions to mitigate radiation-induced severe myelosuppression requires accurate individual dose-estimates. Research initiatives should include developing better individual dosimetry using computational, physical, and biological dosimetry which need to be rapidly available and usable by first responders [69–71]. These efforts are underway in the US and across laboratories globally.

In this review, we focused on sargramostim but noted other similar drugs approved by US FDA to treat H-ARS. DiCarlo et al. reported proceedings of a workshop on repurposing old drugs as well as discussions for developing new agents [72,73]. During a radiation public health emergency, access to molecularly cloned myeloid growth factors and other therapies likely will be limited. To address this deficiency, the US National Institute of Allergy and Infectious Diseases (NIAID) partnered with the Radiation Injury Treatment Network (RITN) to explore the use of growth factors and other cytokines as a medical countermeasure [11,50]. Both workshops included representatives from government, industry, and academia who addressed operational issues.

Experimental data indicate mortality from a standardized skin burn increases in radiated mice [74]. Also, data from Hiroshima and Nagaski indicate most deaths from the A-bombs were from percussive forces, superfires, and projectiles rather than radiation [75]. Thus, the use of drugs to mitigate radiation-induced damage to the hematopoietic tissues is only part of the solution [76]. Other tissues and organs are affected by radiation as well as non-radiation-induced trauma including percussive, thermal, and chemical injuries. The mortality data for radiation combined injuries are complex and certainly clouds assessment for improving patient outcomes. Targeting multiple mechanisms, pathways and tissues and organs would hopefully save lives [77].

7. Conclusions

The treatment of humans exposed to acute, high-dose, and high-dose-rate, whole-body ionizing radiation is a complex medical undertaking [4,50,78,79]. If the radiation dose is very high and the exposure uniform, sargramostim therapy may be ineffective. In contrast, if the radiation dose is lower or there is partial or complete shielding of some bone marrow-bearing areas such as the hip or vertebrae, there may be no need to give this treatment. As noted above, it is difficult to estimate the contribution of concurrent injuries when within the narrow window of a few days of radiation exposure. Determining if the exposure was uniform and assessing shielding effect and extent of concurrent injuries are key. We and other investigators previously have described these complexities [13,14,45,50,80]. We suggest persons exposed to 3–10 Gy ionizing radiation are reasonable candidates to receive sargramostim therapy [21,25,33–35].

The preclinical nonhuman primate data for giving sargramostim discussed above strengthen the conclusion for the safety and efficacy of giving this agent post-exposure. In this highly controlled setting, when the acceleration of bone marrow recovery occurred, survival was improved [35]. Although we emphasize data from humans cannot be critically evaluated for reasons we discuss, the weight-of-evidence favors giving sargramostim to appropriate candidates such as persons exposed to 3–10 Gy ionizing radiation [13]. Use of other supportive interventions are also important including parenteral fluids, RBC- and platelet-transfusions, antimicrobial drugs given either preventively or therapeutically, parenteral nutrition, romiplostim, other interventions such as burn care, and possibly chelating drugs when a part of the exposure is internal. A detailed discussion of HCT, radioprotective drugs, and biological molecules given immediately after radiation exposure is beyond the scope of our review.

In nonhuman primate models of H-ARS, sargramostim therapy did not include concomitant hematologic support such as blood component transfusions. In contrast, these added interventions were used in the nonhuman primate studies supporting the approval of filgrastim and pegfilgrastim. Our review of available literature revealed that there are no peer-reviewed publications on adequate and well-controlled nonhuman primate animal efficacy studies supporting filgrastim and pegfilgrastim in the absence of blood transfusions. The US FDA granted approval in the label for romiplastim, and Wong et al. [81] reported that no blood transfusions were given. Sargramostim has shown efficacy in an adequate and well-controlled animal study when given up to 96 h after exposure and in both male and female subjects [34]. In contrast, filgrastim and pegfilgrastim have not been shown effective when given more than 24 h after exposure, and the data supporting their approval were solely generated in male animals [38–41] (Table 1). Sargramostim is effective after LD_50/60-60 and LD_70/85-60 exposures [33–36] and the ability to achieve a survival benefit with sargramostim up to several days post-irradiation is a significant advantage especially in light of the logistical challenges that are expected in the aftermath of a nuclear incident [49,82].

‘When human efficacy studies are not ethical and field trials are not feasible, FDA may rely on adequate and well-controlled animal efficacy studies to support approval of a drug or licensure of a biological product under the Animal Rule’ [44]. We base our recommendations for the use of sargramostim in nuclear and radiation accidents on biologic considerations including the growth of myeloid cells in vitro, on data from adequate and well-controlled animal efficacy studies, and on data in humans in other settings of severe myelosuppression. As noted above, approval for filgrastim and pegfilgrastim was based on animals receiving blood transfusions, unlikely after nuclear and radiation accidents. Further, we note the added benefit for sargramostim lowering mortality even if given later after exposure than for filgrastim and pegfilgrastim that required administration within 24 h.

8. Expert opinion

The threat of radiation and nuclear accidents and incidents is increasing. For example, tactical nuclear weapons that could be used on the battlefield in limited wars have been developed by the US and Russian Federation, making a nuclear exchange more plausible compared with the time when there were only strategic nuclear weapons. Also, the threat of nuclear terrorism has increased substantially. How to treat victims of these potential incidents who have experienced severe myelosuppression from exposure to acute, high-dose, and high-dose-rate ionizing radiation is controversial. Obviously, it is impossible to conduct randomized clinical trials under real life conditions and experts must rely on surrogate data. These include in vitro biological effects of drugs such as molecularly-cloned hematopoietic growth factors like sargramostim, experiments in animals exposed to high-dose and high-dose-rate ionizing radiation and given molecularly-cloned hematopoietic growth factors, and limited data from uncontrolled phase 2 studies of victims of prior radiation, nuclear accidents and incidents.

Goyal and coworkers [83] performed a machine-learning analysis from 501 nonhuman primates exposed to TBI and identified white blood cell (WBC) count to be predictive as an early marker for risk of death, while WBC count, platelets and reticulocytes were important predictors beyond 7 days after exposure. Machine learning provides a unique and objective method to analyze longitudinal data pooled from different studies for the discernment of biomarker-mortality relationship. These results potentially can facilitate development of medical countermeasures and inform efficient medical management of H-ARS [83].

There are large US Government investments in development of many approaches to save lives after radiation exposures during a public health emergency. Emergence and discussion of these more experimental or clinical data to support safety and efficacy of the potential interventions we discuss, including pharmacokinetic and pharmacodynamic bridging from animal models and radiation damage mechanism of action studies, are beyond the scope of this manuscript. Our recommendation that sargramostim is a promising option follows from it being likely to be implemented in the event of a large-scale radiation or nuclear accident or incident in the minimal supportive care setting, i.e. where infrastructure will be challenged or lacking, and subjects and investigators will be exposed to extraordinary threats [50]. Further progress treating radiation accident victims focuses in several areas including better computational, physical and biological dosimetry to improve accuracy of individual dose estimates, and continued study of drugs which given soon after acute radiation exposure might prevent, lessen the severity, or reverse radiation-induced severe myelosuppression, or reverse radiation-induced damage to the skin, gastro-intestinal tract, kidneys, lungs, or combination of organs. However, the most important and effective progress we hope for are efforts to prevent people from being exposed to acute, high-dose, and high-dose-rate ionizing radiation. Progress requires international treaties further reducing strategic nuclear weapons stockpiles, constraints on developments and use of tactical nuclear weapons and measures to anticipate and prevent nuclear terrorism [6]. Efforts should be made to enforce existing treaties and prevent new states from developing nuclear weapons. Although the focus of our article is on how to respond to a nuclear or radiation incident or accident, prevention of these incidents should be our aim.

Article highlights

• Threats of radiation and nuclear accidents/incidents and nuclear terrorism are increasing. The best treatment for victims experiencing severe myelosuppression from exposure to acute, high-dose, and high-dose-rate ionizing radiation is not established.

• Conducting prospective, randomized clinical trials in victims of radiation exposure clearly is not possible for many reasons including a low incidence rate, unpredictability of incidents from year-to-year and inability to predict where incidents may occur. Further, the fact is that incidents will occur where infrastructure will be challenged or lacking, and subjects and investigators will be exposed to extraordinary threats. Because of the rarity and the overwhelming pragmatic and logistic issues complicating these incidents, we must rely on surrogate data from in vitro, non-clinical and limited, historical data from victims of nuclear accidents and incidents.

• Herein we note and briefly comment upon unapproved products but focus on those agents that have been approved, compare them, and comment on treatment gaps. We adhere to the theme of products approved by the United States Food and Drug Administration (US FDA) under the ‘Animal Rule’ (US Congressional Record; 21 CFR 601.90-95).

• We discuss in detail the recombinant myeloid growth factor sargramostim (rhu GM-CSF) that has been used clinically and displays a favorable benefit-to-risk ratio suggesting it be given soon after exposure.

• Unmet needs include dosimetry for accuracy of individual dose exposure, and better agents for use soon after acute radiation exposure to prevent, lessen the severity, or reverse radiation-induced skin, GI tract, lung, and other organ damage.

This box summarizes key points contained in the article.

Declaration of interest

HM Lazarus is a paid consultant to Partner Therapeutics and has stock options and is a paid consultant to Pluristem Therapeutics. RP Gale is a consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd. RP Gale received funds from Partner Therapeutics for consulting within the past 3 years but none in relation to this publication. J McManus is an employee of and has stock options for Partner Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

The authors contributed equally to design and preparation of the typescript, take responsibility for the content and agree to submit for publication.

Acknowledgments

RP Gale acknowledges support from the United Kingdom National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme, Newcastle University.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Partner Therapeutics, Inc. funded the open access fees.