Gas Plasma Exposure of Glioblastoma Is Cytotoxic and Immunomodulatory in Patient-Derived GBM Tissue

Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant adult brain tumor. Therapeutic options for glioblastoma are maximal surgical resection, chemotherapy, and radiotherapy. Therapy resistance and tumor recurrence demand, however, new strategies. Several experimental studies have suggested gas plasma technology, a partially ionized gas that generates a potent mixture of reactive oxygen species (ROS), as a future complement to the existing treatment arsenal. However, aspects such as immunomodulation, inflammatory consequences, and feasibility studies using GBM tissue have not been addressed so far. In vitro, gas plasma generated ROS that oxidized cells and led to a treatment time-dependent metabolic activity decline and G2 cell cycle arrest. In addition, peripheral blood-derived monocytes were co-cultured with glioblastoma cells, and immunomodulatory surface expression markers and cytokine release were screened. Gas plasma treatment of either cell type, for instance, decreased the expression of the M2-macrophage marker CD163 and the tolerogenic molecule SIGLEC1 (CD169). In patient-derived GBM tissue samples exposed to the plasma jet kINPen ex vivo, apoptosis was significantly increased. Quantitative chemokine/cytokine release screening revealed gas plasma exposure to significantly decrease 5 out of 11 tested chemokines and cytokines, namely IL-6, TGF-β, sTREM-2, b-NGF, and TNF-α involved in GBM apoptosis and immunomodulation. In summary, the immuno-modulatory and proapoptotic action shown in this study might be an important step forward to first clinical observational studies on the future discovery of gas plasma technology’s potential in neurosurgery and neuro-oncology especially in putative adjuvant or combinatory GBM treatment settings.

Cold atmospheric plasma (CAP) treatment increased reactive oxygen and nitrogen species (RONS) levels in tumor samples obtained from patients with low-grade glioma

“…Our study highlights the potential of CAP as a putative adjunct or combinational therapy in lowgrade glioma treatment to improve surgical outcomes by selectively targeting cancer cell death. It is in line with previous studies where they highlighted the effectiveness of CAP jet in promoting cell cycle arrest, apoptosis, and immunomodulation in tissue samples obtained from glioblastoma and basal cell carcinoma patients [54,55].…”

Comparative assessment of direct and indirect cold atmospheric plasma effects, based on helium and argon, on human glioblastoma: an in vitro and in vivo study

“…Based on the calculated IC50 values, the optimal exposure times were 70.15 and 138 s at the 48-h post-treatment time point for direct and indirect helium CAPs, and 202 and 116 s at the 72-h post-treatment time point for direct and indirect argon CAPs, respectively. This confirms previous studies 5 , 34 , which revealed that the effect of CAP on cell death is influenced by the exposure time and the duration of cultivation after treatment.…”

“…Our previous study also exhibit that plasma treatment can be used as an effective and efficient method to treat the GBM cancer 29 . Based on these preclinical studies, CAP has holds great promise for clinical applications in GBM treatment 5 , 10 , 27 , 30 – 34 . However, these studies are still in the preclinical phase, and determining the optimal dose and duration of CAP treatment is necessary for complete GBM cure.…”

Medical gas plasma technology: Roadmap on cancer treatment and immunotherapy

“…Such hot devices are sometimes also called by names known in ‘cold’ plasma medicine, such as Neutral Argon Plasma or PlasmaJet (NCT02376231, NCT049004042, NCT01596985, NCT04355312). In turn, cold gas plasma treatment of patient-derived tumor tissues elicits apoptosis [ [194] , [195] , [196] ]. Some companies marketing these electrosurgical devices started a few years ago to promote cold modes of their equipment.…”

“…About the latter, ex vivo gas plasma treatment of primary tumor tissues has been found to change the secretion profiles markedly when compared to untreated controls if the tumor tissue was cultured for several hours post gas plasma exposure. This was found for all tumor types investigated, i.e., melanoma [ 194 ], cutaneous SCC [ 196 ], basal cell carcinoma (BCC) [ 196 ], glioblastoma [ 195 ], breast cancer [ 202 ], and urothelial (bladder) cancer [ 203 ]. Transcriptomic analysis of the latter also revealed that such changes are the consequence of changed signaling pathways induced by gas plasma treatment rather than merely reflecting the loss of, e.g., the number of viable cells that would participate in cytokine secretion and binding and/or uptake.…”