The logic behind Immunotherapy is to make use of the immune system to destroy cancer cells. The immune system is a complex system inside the human body, that helps to identify and fight diseases or infections. In fact scientists have discovered that the immune system can also protect the body against cancerous cells. Therefore Immunotherapy helps the immune system to recognize and fight these threats [1]. Usually immunotherapy is used if the tumor is resistant to radiation or chemotherapy, thus being more targeted and usually prducing other side effects. This chapter covers how immune cells can detect cancer cells, the three approved therapies and gives an outlook on cancer vaccines, another targeted approach.

Basic Priniciple Of Immunotherapy[2]

Detection Of Cancer Cells

The part of the immune system that is responsible for the destruction of foreign cells are Cytotoxic T-Cells, also known as killerT-cells. The immune system identifyies cells as foreign via the help of antigens. So normal cells carry a self antigen which identifies them as belonging to the body [3] Cancer cells carry these self antigens as well as cancer associated antigens, that trigger killer T-cells. However due to several factor it is diificult for the immune system to accurately determine these antigens:

• the antigens are just slightly altered versions of self antigens
• cancer cells undergo genetic changes
• cancer cells can evade killer T-cells

Approved Therapies

Currently there are two approved immunotherapies for brain tumor treatment - Bevacizumab (Avastin®) for adults  with recurrent glioblastoma and dinutuximab (UNITUXIN®) for children with neuroblastoma [4]. Both rely on on monoclonical antiboides Monoclonical antibodies recognize specific molecules on the surface of cancer cells and bind to them. This results in the immune destruction of the target molecules. Another targeted therapy is Everolimus (Afinitor) [5].

Bevacizumab [6]

Bevacizumab antiobodies target vascular endothelial growth factor (VEGF), a protein that helps tumors form new blood vessels to get nutrients (angiogenesis). This helps to slow down the growth of certain tumors, especially glioblastomas (Tumor Types), after a surgical removal (Surgery). Unfortunately it does not expand the livespan of people. It is also used during steroid treatment to reduce the dose of the steroids.

Bevacizumab is usually injected intravenously every two weeks. It comes with common side effects like high blood pressure, bleeding and low white blood cell count. Under rare circumstances blood clots, internal bleeding, heart problems, holes in the intestines and slow wound healing can occurr as serious side effects.

Dinutuximab (Unituxin) [7] [8]

Dinutuximab antibodies targets glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. This binding marks neuroblastoma cells for the immune system so they can be destroyed. Dinutuximab is given to children in the age of 12 months to 17 years who have a high risk neuroblastom. It is only given if these children responden to previous chemotherapy (Chemotherapy) and subsequently underwent a stem cell therapy plus a bone marrow cleaning. It is intravenously applied with 3 other medications (GM-CSF, Interleukin-2 and Isotretinoin). Studies showed that 80% of patients treated with dinutuximab were still alive after 3 years compared to 67% who weren't.

However 26% percents of patients who received this medication had serious and lifethreatening infusion reactions. Furthermore dinutuximab is neurotoxic and can cause severe pain. Therefore it should be given only with pain medication. The approval for unituxin was withdrawn in early 2017 for the EU where now only Dinutuximab Beta is allowed. To find out what is necessary for a drug to be approved see Clinical Trials.

Everolimus (Affinitor) [6]

Everolimus works by blocking a cell protein known as mTOR, which normally helps cells grow and divide into new cells. It can slow down or shrink astrocytoma (Tumor Types) that can not be completely removed via surgery. However as Bevacizumab it is not clear if it can expand the livespan of the patient. Everolismus is FDA approved and taken as a pill once a day.

It comes with common side effect like sore mouth, nausea or diarrhea. Under rare circumstance it can damage the lungs, leading to shortness of breath and other problems.

Cancer Vaccines [9]

Vaccines are made up of harmless microbes that stimulate an immune response to the infection and thus the immune system can remember this infection to prevent it from spreading again. Cancer Vaccines can be used preventive or as a form of immunotherapy to fight existing cancerous cells. Preventive vaccines target infections or agents that cause or contribute to the development of cancerous cells. In the United States Human Papillomavirus and Hepatits B vaccines belong to these preventions.

The FDA approved the first cancer treatment vaccine in 2010 which is the sipuleucel-T used for men with metastatic prostate cancer.

Unfortunately there is not yet a vaccine for brain cancer, though there are several clinical trials running to research this subject [10].

Bibliography

1. Pardoll D. Cancer immunology. In: Abeloff M, Armitage J, Niederhuber J, Kastan M, McKenna W, eds. Abeloff's Clinical Oncology. 4th ed. Philadelphia: Churchill Livingstone; 2008.
2. http://newsroom.cumc.columbia.edu/blog/2015/03/12/immunotherapy-new-hope-patients-advanced-lung-cancer/
3. Murphy KM, Travers P, Walport M, editors. Janeway's Immunobiology. 7th ed. New York: Garland Science, 2007.
4. https://www.cancerresearch.org/patients/patients/cancer-types/brain-cancer
5. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet#q8
6. https://www.cancer.org/cancer/brain-spinal-cord-tumors-adults/treating/targeted-therapy.html
7. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Summary_for_the_public/human/002800/WC500192842.pdf
8. https://www.unituxin.com
9. https://www.cancer.gov/about-cancer/causes-prevention/vaccines-fact-sheet#r1
10. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=6235812&vers=1