Intervention by Physical Means Radiation Hyperthermia Electrochemical Therapy

Ionizing radiation therapy (RT) is an important local modality for the treatment of cancer. RT is largely based on the ability to kill cancer cells by direct cytotoxic effects. A large body of evidence is accumulating on the ability of RT to modify the tumor microenvironment and generate inflammation. This might have far reaching consequences regarding the response of a patient to treatment, especially if radiation induced tumor cell kill were to translate into the generation of effective antitumor immunity. Data from pre-clinical studies provide the proof of principle that different immunotherapeutic strategies can be combined with RT to enhance antitumor effects. An adenovector expressing TNF-a under the control of an irradiation-inducible promoter was developed. A recently published phase I study in patients with solid tumors demonstrated safety and a greater response in lesions treated with a viral vector and RT compared with RT alone [104]. Another clinical trial was designed to examine whether vaccination with Pox-virus encoding prostate specific antigen could be combined with standard external beam RT in patients with prostate cancer. The trial suggests that this combination can generate an antigen cascade with development of T cells directed against other TAAs then those present in the vaccine [105], a phenomenon recently proposed to play a crucial role in determining the therapeutic efficacy of immunotherapy [106, 107].

Hyperthermia application to the site of tumors is another physical means of altering the tumor microenvironment. An elevated local temperature of 39-44 °C can affect tumor cell survival [108] and it can make this environment more susceptible to infiltration by viruses, NK cells, DCs or T-lymphocytes. The attraction of oncolytic viruses in such pre-treated tumor after local or loco-regional virus inoculation may cause NK cell attraction and DC activation due to virus-derived danger signals, interferons, cytokines and chemokines. A rise in temperature as in fever was recently shown to trigger enhanced lymph node recruitment of lymphocytes by augmenting high endothelial vesicle expression of the homing molecules ICAM-1 and CCL21 [109].

Several authors have recently reported encouraging results from electro-chemical treatment (EChT) in malignant tumors [110]. The electric field in a tumor microenvironment causes a flux of interstitial water, electro-osmosis, from the anode toward the cathode, since the water-molecules act like a dipole. Consequently, the tissue surrounding the anode dehydrates while edema is obtained around the cathode. Some results suggest that secondary cell destruction is caused by necrosis with cathodic EChT and apoptosis or necrosis with anodic EChT. In China, more than 15,000 patients with various malignant tumors have been treated with this procedure over the last 15 years [111]. The application of electric pulses and currents to a tumor microenvironment can help to increase the effectiveness of uptake of cytotoxic drugs and also that of immune activating agents such as DNA plasmids, TLR activators, etc.

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