Cytostatic hypothermia and its impact on glioblastoma and survival

Abstract

AbstractNovel therapeutic approaches are needed for patients with glioblastoma (GBM) who otherwise have limited options. One approach, cryogenic hypothermia, can ablate localized tumors but is a double-edged sword against tumors infiltrating otherwise healthy tissue. Instead, here we studied and deployed local, non-freezing ‘cytostatic’ hypothermia to stunt GBM growth. We first investigated three grades of hypothermia in vitro and identified a cytostatic window of 20–25°C. We determined that 18 h/d of cytostatic hypothermia can be sufficient to prevent growth. Cytostatic hypothermia resulted in cell cycle arrest, reduced metabolite production and consumption, and reduced inflammatory cytokine synthesis. Next, we designed a device to deliver local cytostatic hypothermia in vivo in two rodent models of GBM: utilizing the rat F98 and the human U-87 MG lines. Local hypothermia more than doubled the median survival of F98 bearing rats from 3.9 weeks to 9.7 weeks. Two rats survived through 12 weeks. No loss of U-87 MG bearing rats was observed during their study period of 9 weeks. Additionally, cytostatic hypothermia was synergistic with TMZ chemotherapy in vitro. Interestingly, CAR T cells also retained significant cytotoxicity under these temperatures in vitro. Unlike modern targeted therapeutics, cytostatic hypothermia affects multiple cellular processes. Thus, irrespective of the host species (rodent or human), it could slow tumor progression and the evolution of resistance. Our studies show that this approach lengthens survival without chemical interventions. However, it may also provide time and opportunities to use standard concomitant, adjuvant, and novel cytotoxic treatments. Thus, cytostatic hypothermia could have a valuable role among the limited options available for the treatment of glioblastoma.