This part gives an overview regarding newly established methods in brain tumor treatment.
Alternating electric field (AEF) therapy
The usage of alternating electric fields (AEF) is a new type of tumor treatment. Alternating electric fields are inserted at 100 – 130 kHz into the tissue via multiple electrodes at the body surface and harm the growth of cells. Quiescent cells are not harmed by the AEFs, whereas proliferating cells are disturbed in their mitosis and may even be killed (programmed cell death, apoptosis). In a laboratory environment, the effect on proliferating cells can be shown within a duration of 24 h, when the alternating electric field is applied to the cells. [1] Alternating electric fields for the treatment of tumors were developed by the Israeli company Novocure using the name Tumor Treating Fields (TT fields, TTF). [2]
The company Novocure developed a device for the treatment of glioblastoma (GBM) using AEFs. In 2011, this device received an approval by the U.S. Food and Drug Administration (FDA), if the GBM recurred or progressed after chemotherapy. After a clinic trial in 2015, this device can be used as part of a standard treatment (i.e. surgery, radiation, chemotherapy). In this trial, patients with GBM were treated with a chemotherapy drug and the alternating electric fields or only the chemotherapy drug. It could be shown that patients that additionaly received the alternating electric fields lived three months longer. [3]
The mode of action can be specified as follows: If the cell and the cell division process are aligned along the electric flux lines, AEFs result in the arrest of proliferation and cell destruction. The alternating electric fields disrupt the proper formation of the mitotic spindle, as seen in figure 4, part A: the microtubule tip and the electric field exert forces on the dimers that form the microtubule. If a dimer is less than 14 nm away from the microtubule tip (dimer a), it aligns with the microtubule. If it is more than 14 nm away from the microtubule tip, it aligns according to the electric field and therefore the mitosis process is disturbed. Figure 4, part B shows a finite element simulation of the electric flux lines in a quiescent cell (left) and a cell during mitosis (right). On the left, the lines are equidistant, not yielding any forces on the cell elements. On the right the electric flux lines are denser in the cleave furrow. These denser flux lines indicate an electric force on polar and charged entities, which are pulled to the furrow. Especially cytoplasmatic organelles move to the furrow, disturbing the mitosis process and maybe resulting in cell destruction. [1] This explains the need for multiple electrodes, too: it is necessary to exert an electric field in as many directions as possible to disturb the tumor cells in all their orientations.
AEFs possess more favorable side-effects than chemotherapeutic agents, while having a similar efficacy. They do only have limited systemic effects (in contrast to intense systemic effects by chemotherapeutic agents), the most common side-effect is contact dermatitis between skin and electrode. [4]
Figure 4: mode of action of alternating electric fields on cells
Targeted therapy
Conventional methods (especially chemotherapy) have difficulties targetting only the tumor cells, resulting in severe side-effects. Therefore new methods are reserached and already established that target specific molecular pathways of tumors. Some tumor types each possess a unique molecular driver, which can be used against them with high effectiveness. This is especially true for leukemia (blood cancer).
Unfortunately, big solid tumors (e.g. brain tumors) do not possess a clear molecular driver. Methods targetting different aspects of the tumor cells of solid tumors are currently researched with slight successes. [6]
There is an intersecting set between targeted therapy methods and immunotherapy methods, if the immunotherapy methods use specific molecular drivers called immune checkpoints (cp. next section).
Immunotherapy [5]
The immune system (i.e. classes of leucocytes of the blood, e.g. T cells and antibodies) attacks unknown substances it finds in the body. As cancer cells start as normal cells which start uncontrolled proliferation, it is much harder for the immune system to recognize and attack these cells.
Immunotherapy uses the patient’s own immune system to fight cancer. The are two possible ways to do this: either via stimulation of the immune system to intensify its work against the tumor or by inserting immune system components from outside the body. There are many different types of immunotherapy, some methods may strenghten the patient’s immune system in general and some methods may be specifically trained against cancer cells.
The main types of immunotheraphy are:
- Monoclonal antibodies: Artificially created immune system proteins that are designed to attack specifc parts of cancer cells.
Immune checkpoint inhibitors: Some cancer cells avoid being attacked by the immune system by using specific proteins to trick the immune checkpoints (receptors on T cells that decrease or increase the T cell’s actions). Immune checkpoint inhibitors mark these specific proteins and therefore point the immune system towards these cancer cells.
Cancer vaccines: Vaccines that target viri that are responsible for the outbreak of cancer (e.g. human papilloma virus (HPV) and chronic infection with hepatitis B virus (HBV)).
Non-specific immunotherapies: treatments that enhance the general immune system functionality and intensity.
Combined targeted and immunotheraphy [7]
The combination of targted therapy with immunotherapy (i.e. monoclonal antibodies and non-specific immunotherapies) can have a strong synergy. While targeted therapy primarily destroys the tumor cells, immunotherapy focuses on teaching the patient’s own immune system what to do against cancer cells in principle. Therefore an immunotherapy may have very good long-term protection against the recurrence of tumor cells.
The interaction between targeted therapy and immunotherapy must be studied in detail, though. There is a difficult interaction between the dead tumor cells of the targeted therapy, immunotherapy antibodies and the patient’s immune system.
In summary, there is a big opportunity to create personalized treatments with combining targeted therapy and immunotherapy.