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Boosting the immune system can improve cancer prevention and treatment

The activation of the body’s immune system to fight cancer is not only a promising therapeutic concept, but is already used in medical practice. The first immunotherapies have been approved and many more are either in the experimental stages or already undergoing clinical testing. Vaccines to prevent certain types of cancer are already being used successfully around the world.

Regulatory T cell under the scanning electron microscope. © DKFZ

Cancer immunotherapy aims at using the T lymphocytes (T cells) of the immune system, which are responsible for producing antibodies and eliminating cells infected with bacteria or viruses, in order to provoke an immune response against a cancer. Research into using this impressive therapeutic approach has been going on for many decades. However, many attempts have failed because tumour cells have sophisticated strategies that prevent them from being recognised and destroyed by the T lymphocytes. For example, cancer cells secrete specific substances to keep T lymphocytes at bay or prevent them from intruding into the tumour tissue.

Regulatory T cells are a specific population of T cells that maintain self-tolerance to the body's own tissue in order to prevent autoimmune diseases and allergies. However, this means that they also suppress the body's ability to defend itself against tumour cells. Tumour cells carry immunosuppressive molecules on their surface that ensure that the body's own cells are not attacked by immune cells. However, in order for T cells to be able to recognise and attack a tumour, they need to have features that make them look different from healthy cells. It is not easy to identify suitable tumour antigens for use as target structures for vaccines or other immunotherapies due to the fact that tumour cells differ greatly from person to person as well as within a single tumour.

A breakthrough in cancer immunotherapy is close

Numerous strategies for overcoming the aforementioned difficulties have been developed and many experts believe that a breakthrough in cancer immunotherapy is close: T cells are genetically modified to be able to recognise specific structures in cancer cells; antibodies that inhibit the immunosuppressive molecules on cancer cells are used to induce a specific immune response against a cancer; the ability of the cancer cells to evade the body's immune system can now be overcome by suppressing messenger substances that are secreted by the tumour, thus making the tumour visible to the immune system. Patients with advanced cancer usually have a weaker immune response, and attempts are being made to strengthen the immune system by stimulating the formation and proliferation of T lymphocytes. A combination of different approaches seems to have the best effect.

A cancer cell spreads in the body by way of an opening in the blood vessel wall. If it is not recognised and eliminated by the body’s immune system, it can settle in an organ and establish itself, i.e. form a metastasis. © DKFZ

An immunotherapy for treating metasising melanoma (black skin cancer), which is based on an antibody against a checkpoint protein on the surface of cytotoxic T cells that suppresses an immune response, has already been approved for human application. Clinical studies to test the efficiency of immunotherapies for the treatment of advanced kidney and lung cancer are under way. A therapeutic vaccine for treating a specific type of brain tumour, i. e. low-grade gliomas that are characterised by a specific mutation in a key enzyme, is also undergoing clinical testing.

The company Vaximm is currently testing vaccines for the treatment of pancreatic cancer by targeting the tumour vasculature, which is essential for tumours to grow. Without a blood supply, the tumour cells die off. Other researchers are screening proteins on the surface of tumour cells or T helper cells for the presence of epitopes, i.e. specific peptide structures that induce an immune response and are excellent immunotherapy targets. Such peptides can then be synthesised in the laboratory and screened using bioinformatics and mass spectrometric tools.

Modified, genetically optimised antibodies and antigen-antibody complexes such as those that were previously only used as vaccines against infectious diseases, can also be used for cancer therapy, under certain conditions. Immunotherapies for the treatment of leukaemias and B-cell lymphomas have shown promising results.

Unfortunately, existing immunotherapies do not help all patients equally, and it is difficult to find out why. Some tumours have been resistant to all attempts at immunotherapy, and research is under way to change this by tailoring treatment to the personal requirements of individual patients, as is done with chemotherapies. This can only be achieved with reliable biomarkers. A test has been developed that shows whether a sought-after tumour-specific peptide is presented on the surface of tumour cells in a form that T cells can recognise. This approach might help determine prior to treatment whether a patient is likely to respond or not to the cancer vaccine.

In Germany, young girls can now protect themselves from cervical cancer. © NCI

From prophylactic to therapeutic cancer vaccines

The first vaccine against human cancer was one that effectively prevents infection with high-risk type 16 and 18 papillomaviruses (HPV), which Harald zur Hausen had shown to be the cause of cervical cancer. Since the approval of the first HPV vaccine in 2006 (a second one was licensed in 2009), millions of girls and young women in America, Europe and Australia have been immunised and the incidence of cervical cancer has dropped dramatically in these countries. The vaccines are purely prophylactic, and therefore ineffective in women infected with HPV who have potentially already developed cervical cancer. Carcinogenic papillomaviruses may also lead to the development of skin cancers and other mucous membrane neoplasias. A prophylactic and therapeutic vaccine against white skin cancer (which occurs quite frequently) has already been shown to be effective in the animal model; clinical trials will be undertaken to assess the efficiency of the vaccine in people with compromised or weakened immune systems that are at particular risk of developing cancer. As for the development of therapeutic vaccines against cervical cancer, research is currently specifically focused on identifying suitable HPV epitopes on the surface of virus-transformed tumour cells and T helper cells.

In the past, vaccine development was mainly geared towards infectious diseases caused by viruses or other microbes. As viruses have also been shown to be one of the most important risk factors for cancer development in humans, research has therefore focused specifically on the development of vaccines that prevent or treat cancers caused by viral pathogens. In addition to HPV, these include Epstein-Barr virus (EBV) which leads to the development of different types of carcinomas. In order to develop an EBV vaccine, EBV surface proteins were used for the recombinant production of antigen-antibody complexes for activating – by mimicking an EBV infection – the immune system against B-cell lymphomas. This was the first time ever that such complexes were used for this purpose. Previously, antigen-loaded antibodies were only used for vaccines designed for immunisation against infectious diseases. Another revolutionary cancer immunotherapy approach is the development of vaccines based on messenger RNAs that code for tumour antigens and stimulate the immune system to produce macrophages and antibodies against the tumour. Curevac, a biotechnology company based in Tübingen, has developed an RNA-based vaccine for treating metastasing prostate carcinoma which is already undergoing clinical phase IIb testing.

 

Glossary

  • Antigens are foreign substances that stimulate the immune system to produce antibodies.
  • Antibodies are blood proteins (immunoglobulins) which are produced by the B lymphocytes in response to disease. They recognise foreign substances that have entered the body (e.g. bacteria) and help the body fight against a particular disease and develop an immunity to that disease.
  • A gene is a hereditary unit which has effects on the traits and thus on the phenotype of an organism. Part on the DNA which contains genetic information for the synthesis of a protein or functional RNA (e.g. tRNA).
  • Pathogenity is the ability to cause a disease. One differentiates between human, animal, and plant pathogens which specifically cause a disease in either humans, animals or plants.
  • Phage is the short form for bacteriophage – a virus that reproduces in bacteria.
  • Recombination is the process in which DNA is recombined. As a natural process, recombination takes place in sexual reproduction during meiosis. In vitro recombination involves the joining of DNA molecules of different origin using recombinant DNA technologies.
  • Ribonucleic acid (abbr. RNA) is a normally single-stranded nucleic acid, which is very similar to DNA. It also consists of a sugar-phosphate backbone and a sequence of four bases. However, the sugar is a ribose and instead of thymine, RNA contains uracil. RNA has got various forms and functions; e.g. it serves as template during protein synthesis and it also constitutes the genome of RNA viruses.
  • Screening is a systematic test procedure that is used to identify certain characteristics within an array of samples or persons. In molecular biology screening is used to filter a designated clone out of a gen bank, for example.
  • Transformation is the natural ability of some species of bacteria to take up free DNA from their surroundings through their cell wall. In genetic engineering, transformation denotes a process which is often used to introduce recombinant plasmids in E. coli, for example. This is a modified version of natural transformation.
  • A vaccine is a preparation of dead or weakened pathogens (or of derived antigenic determinants) used to induce immunity against the pathogen.
  • A virus is an infectious particle (no cell!) consisting of a protein envelope and a genome (DNA or RNA). To be able to reproduce it depends entirely on the metabolism of living cells of host organisms (e.g., bacteria for phages, liver cells for Hepatitis A-virus).
  • Chemotherapy is the treatment of diseases, especially cancer, by means of chemotherapeutic agents (pharmaceuticals that inhibt the growth of (cancer) cells).
  • A tumour is a swelling of a tissue caused by abnormal cell growth, which can be benign or malignant. Benign tumours are local swellings, whereas malign tumours may seed off and spread into other tissues, causing secondary growths (metastases).
  • Immunotherapy is a kind of treatment for diseases, which involves and utilises the immune system. Immunotherapeutical methods are applied amongst others to treat allergies, cancer, infections and autoimmune diseases.
  • Lymphomas are malign tumours of the lymphatic system. They result from ongoing monoclonal production of lymphocytes. Lymphomas can be categorized into Hodgkin's lymphomas and non-Hodgkin lymphomas.
  • Leukaemia is a malign disease (cancer) of the hematopoietic system. It disturbs the generation of blood cells in the bone marrow by increased formation of degenerated white blood cells and their precursor cells. Other components of the blood are displaced. This leads to anaemia, infections and bleedings and finally to the death of the affected person, if leukaemia remains untreated.
  • The pancreas is a gland organ in the upper part of the belly. On the one hand, it produces certain digestive enzymes, which are then released into the small intestine, and on the other hand different hormones like insulin and glucagon that are released into the bloodstream.
  • The immune system is the body’s defence system that protects the organism against dangerous pathogens. Furthermore, it destroys abnormal body cells. Those defence mechanisms are build up by a complex interaction of several organs, different cell types and chemical molecules.
  • The toxicity is the poisonousness of a substance.
  • Secretion is the release of a substance or fluid out of tissues or cells with or without glands.
  • Autoimmune diseases are diseases that are characterized by an immune system attacking the own body cells. This is caused by a failure of the immune system to discriminate between self and foreign cells or tissues.
  • An epitope is the part off an antigen that is recognized by an antibody. There are several different epitopes on the surface off an antigen. An antibody specifically binds a single epitope.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.
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