Filgrastim Improves Survival in Lethally Irradiated Nonhuman Primates

Abstract

Treatment of individuals exposed to potentially lethal doses of radiation is of paramount concern to health professionals and government agencies. We evaluated the efficacy of filgrastim to increase survival of nonhuman primates (NHP) exposed to an approximate mid-lethal dose (LD50/60) (7.50 Gy) of LINAC-derived photon radiation. Prior to total-body irradiation (TBI), nonhuman primates were randomized to either a control (n =22) or filgrastim-treated (n =24) cohorts. Filgrastim (10 μg/kg/d) was administered beginning 1 day after TBI and continued daily until the absolute neutrophil count (ANC) was >1,000/μL for 3 consecutive days. All nonhuman primates received medical management as per protocol. The primary end point was all cause overall mortality over the 60 day in-life study. Secondary end points included mean survival time of decedents and all hematologic-related parameters. Filgrastim significantly (P < 0.004) reduced 60 day overall mortality [20.8% (5/24)] compared to the controls [59.1% (13/22)]. Filgrastim significantly decreased the duration of neutropenia, but did not affect the absolute neutrophil count nadir. Febrile neutropenia (ANC <500/μL and body temperature ≥103°F) was experienced by 90.9% (20/22) of controls compared to 79.2% (19/24) of filgrastim-treated animals (P = 0.418). Survival was significantly increased by 38.3% over controls. Filgrastim, administered at this dose and schedule, effectively mitigated the lethality of the hematopoietic subsyndrome of the acute radiation syndrome.

Development of Pediatric Model of Hematopoietic Acute Radiation Syndrome (H-Ars) and Countermeasure Testing Using the Göttingen Minipig

“…In our study, G-CSF resulted in 62.5% survival in the test group compared to 25% survival in the control piglets. This is comparable to 50% and 78.3% survival seen in G-CSF-treated adult minipigs at LD70/30 [11] and G-CSF treated NHPs at LD50/60, respectively [23]. G-CSF increased neutrophil counts after 24 h of administration and kinetics of neutrophil recovery were similar to those observed in pediatric cancer patients with chemotherapy induced neutropenia [24], confirming the potential of the minipig as a model for the human H-ARS.…”

“…Blood samples were collected once before irradiation followed by days 0, 1,3,7,10,14,17,20,23,28,35,42, and 45 post-irradiation. Blood was collected in EDTA tubes and immediately processed for complete blood counts with differentials (CBC/diffs) using the ADVIA 2120 (Siemens Medical Solutions Diagnostics, Ireland).…”

Recombinant interleukin‐12, but not granulocyte‐colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: Evidence for the development of a frontline radiation medical countermeasure

“…These data are significant, given that G-CSF is the treatment currently recommended for individuals exposed to lethal TBI [4], as supported by a single study that demonstrated a benefit for G-CSF when combined with highly intensive, trigger-based medical management [5]. By comparison, our data show that a regimen of 18 daily doses of G-CSF alone, in the absence of other supportive medical interventions, provides no survival benefit over that of the vehicle control.…”

A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part I. Radiation sub-syndromes, animal models and FDA-approved countermeasures

“…Promising radiation countermeasures under development for H-ARS have been tested in NHP for efficacy and pharmacokinetics/ pharmacodynamics. Some important radiation countermeasures tested for efficacy in the NHP model include G-CSF (filgrastim, Neupogen) (Farese et al 2013;, PEGylated G-CSF (PEGfilgrastim/Neulasta) (Hankey et al 2015), CBLB502 (Entolimod) (Krivokrysenko et al 2012(Krivokrysenko et al , 2015, interleukin-12 (HemaMax) (Basile et al 2012;GluzmanPoltorak et al 2014aGluzmanPoltorak et al , 2014b, AEOL 10150 (meso-porphyrin mimetic) (Garofalo et al 2014b), 5-Androstenediol (Stickney et al 2006(Stickney et al , 2007, amifostine (WR2721, Ethyol) (Geary et al 1989), B-190 (Vasin et al 2014) and c-tocotrienol (Singh et al 2016a). …”

“…Radiomitigators include immunomodulating agents such as 5-androstenediol, interleukin-12, G-CSF, PEGylated G-CSF, GM-CSF, and CBLB502 (truncated flagellin), as well as and angiotensin-converting enzyme inhibitors (ACE; captopril) (Seed 2005;Dumont et al 2010;Singh et al 2012Singh et al , 2014aMoulder 2014). Radiation therapeutics are agents administered once symptoms manifest in order to accelerate regeneration of tissue and organs Wagemaker et al 1998;Farese et al 2001Farese et al , 2013Drouet et al 2004;Herodin et al 2007;Dumont et al 2010). G-CSF, PEGylated G-CSF, GM-CSF, and cellular therapy falls under this class (Singh et al 2015a).…”