Gas Plasma Combination Therapies-Promises from Preclinical Oncology Research

Abstract

The absent decline in cancer mortality rates is primarily due to moderate therapeutic efficacy and intrinsic or acquired tumor cell resistance toward treatments. Combining different oncology treatments increases therapy success and decreases the chance of refractory tumor cells. Therefore, combination cancer treatments are the principal paradigm of 21st-century oncology. Physical modalities such as radiotherapy have a long-standing tradition in such combination treatments. In the last decade, another physical principle emerged as a promising anticancer agent: cold gas plasma. This partially ionized gas, operated at about body temperature, emits multiple bioactive components, including reactive oxygen and nitrogen species (ROS/RNS). This technology's multi-ROS/RNS nature cannot be phenocopied by other means, and it capitalizes on the vulnerability of tumor cells within metabolic and redox signaling pathways. Many cancer models exposed to mono or combination gas plasma treatments have shown favorable results, and first cancer patients have benefited from cold gas plasma therapy. The main findings and proposed mechanisms of action are summarized. Considering the specific application modes, this review identifies promising gas plasma combination therapies within guideline-directed treatment schemes for several tumor entities. In conclusion, gas plasmas may become a potential (neo)adjuvant therapy to existing treatment modalities to help improve the efficacy of oncological treatments.

Keywords: CAP; LTP; NTP; chemotherapy; drugs; electrochemotherapy; immunotherapy; ionizing radiation; photodynamic therapy; plasma medicine; radiotherapy.

Figure 1

Gas plasmas’ main biologically active components, device types, and exemplary principle of ROS production. Gas plasma is composed of various physical and chemical gas plasma components with biological activity (left). Gas plasma for medical applications is commonly generated with either atmospheric pressure plasma jets, in which a feed gas (e.g., helium or argon) flowing through a nozzle is excited by applying high voltage, or with dielectric barrier discharge (DBD) devices, where ambient air is excited between two electrodes. Representative drawings of the two device types are shown here (middle). Reactive species causing biological effects like singlet oxygen, superoxide, ozone, nitric oxide, nitrate, hydroxyl radical, and hydrogen peroxide are generated by the reaction of excited gas molecules (e.g., argon gas in a jet device, red square) with oxygen, nitrogen, and water molecules from ambient air (right).

Figure 2

Potential combination treatments using medical gas plasma technology.

Figure 3

Potential mechanism of action on clonal selection through oxidative stress. Image is adapted from ref. [209].

Figure 4

Current and future approaches to use and combine medical gas plasma technology in oncology. Image is adapted from ref. [5].