Electrical Stimulation for Immune Modulation in Cancer Treatments

Abstract

Immunotherapy is becoming a very common treatment for cancer, using approaches like checkpoint inhibition, T cell transfer therapy, monoclonal antibodies and cancer vaccination. However, these approaches involve high doses of immune therapeutics with problematic side effects. A promising approach to reducing the dose of immunotherapeutic agents given to a cancer patient is to combine it with electrical stimulation, which can act in two ways; it can either modulate the immune system to produce the immune cytokines and agents in the patient’s body or it can increase the cellular uptake of these immune agents via electroporation. Electrical stimulation in form of direct current has been shown to reduce tumor sizes in immune-competent mice while having no effect on tumor sizes in immune-deficient mice. Several studies have used nano-pulsed electrical stimulations to activate the immune system and drive it against tumor cells. This approach has been utilized for different types of cancers, like fibrosarcoma, hepatocellular carcinoma, human papillomavirus etc. Another common approach is to combine electrochemotherapy with immune modulation, either by inducing immunogenic cell death or injecting immunostimulants that increase the effectiveness of the treatments. Several therapies utilize electroporation to deliver immunostimulants (like genes encoded with cytokine producing sequences, cancer specific antigens or fragments of anti-tumor toxins) more effectively. Lastly, electrical stimulation of the vagus nerve can trigger production and activation of anti-tumor immune cells and immune reactions. Hence, the use of electrical stimulation to modulate the immune system in different ways can be a promising approach to treat cancer.

Electroporation in Head-and-Neck Cancer: An Innovative Approach with Immunotherapy and Nanotechnology Combination

“…The second important event correlated to EP application is the local activation of immune system cells causing immune response stimulation and immune cytokines production [ 75 , 76 ]. During EP, the uptake of extracellular proteins happens, and consequently, intracellular proteins escape into the extracellular milieu, acting as a source of damage-associated molecular patterns (DAMPs) that potentially induce an immunogenic response [ 77 ].…”

“…During EP, the uptake of extracellular proteins happens, and consequently, intracellular proteins escape into the extracellular milieu, acting as a source of damage-associated molecular patterns (DAMPs) that potentially induce an immunogenic response [ 77 ]. Moreover, under local electric stimulation, it has been reported in vitro that macrophages polarization in M1(pro-inflammatory macrophages) or M2 (anti-inflammatory macrophages) can be modulated; as well as migration, proliferation, and cytokines production from T-cells can be controlled by EFP application [ 75 , 78 ]. In one other work, Arnold et al showed that exogenous electrical fields affected the migration, proliferation, and cytokine production of T cells.…”

“…Vascular lock entraps drugs in the tumor site and slows down their washout. Finally, the effect of tumor cell disruption during EP is enhanced during ECT, which induces greater recruitment of antigen-presenting cells (APCs) and release of damage-associated molecular patterns (DAMPs) that, by activating immune cells interacting with pattern recognition receptors (PRRs), act synergistically in fighting against cancer exploiting immune-response [ 75 , 81 ]. By knowing these, mathematical models and optimization techniques have enabled more effective ECT design and electrodes positioning when considering the effect of tissue inhomogeneity on electric field distribution and, consequently, outcome [ 82 ].…”

“…ECT was implemented with monoclonal antibody to enhance its antitumoral activity; preclinical evidence suggests that the association of ECT with immune-stimulating agents can be an efficient way to cure the targeted malignant tumors and any distant nontargeted tumor nodules, even if it is an undetectable metastasis [ 75 , 125 ].…”

Electrostatic potential difference between tumor and paratumor regulates cancer stem cell behavior and prognose tumor spread

“…Electrical stimulation has been extensively investigated for its potential to modulate immune responses 15 and destroy cancer cells 16,17 (including CSCs 18 ). However, the use of electrostatic potentials for CSC identification, quantification, and migratory studies remains underexplored.…”