Discussion
toxicity
Given the relatively low success rate of novel interventions in oncology,In an initial study, we employed a combination of mathematical and mouse modeling to quantitatively characterize the dynamic heterogeneity and plasticity of GBM radiation responses. We exploited this quantitative understanding to optimize a radiation schedule, which substantially improved survival compared with a standard schedule in a preclinical trial using mouse models.The progression-free (4.4 months) and overall (7.3 months) survival of patients in our clinical trial were similar to those observed in studies of re-irradiation of recurrent GBM treated with conventional schedules.Our study possesses several limitations. First, the treatment-naïve mouse model used in our preclinical study may fail to capture the relevant biology of the heavily pretreated population of patients included in our trial. Second, while we could have benchmarked our treatment regimen against more dose-intensive or stereotactic treatment schedules, we aimed to conduct this first-in-human study as referenced to a well-established regimen (35 Gy in 10 fractions) with no prior reported grade 4/5 toxicity as observed within a prospective, randomized multi-institutional study.In conclusion, we here provide evidence suggesting that a novel radiation therapy schedule, exploiting cell-state plasticity, holds promising clinical potential. We have demonstrated that this novel therapeutic approach is feasible and safe to administer to recurrent GBM patients. We believe that the promise, feasibility, and low cost of our therapeutic strategy warrant further mechanistic investigations using preclinical models to guide a future efficacy trial in patients.