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The story has been all over the news in Germany: a young man with inoperable lung cancer that did not respond to chemotherapy is now doing better and his tumour is shrinking. What happened? He took part in a clinical trial in which immune cells were activated to attack cancer cells. This new approach is called immunotherapy. Is this a revolution in the treatment of cancer patients? And what exactly happens for the immune system to suddenly fight the cancer?
The role of the immune system is to recognise and destroy pathogens like bacteria and viruses. Cancer cells originate from normal tissue and are harder for the immune system to identify as dangerous. Cancer cells develop when cells acquire mutations in their DNA leading to dysfunctional proteins that allow the cells to grow uncontrollably. During the cell divisions that follow, more mutations occur. Some of these mutated proteins can be recognised by the immune system and are called immunogenic cancer antigens. So actually “Immunotherapy” is a normal and common process that occurs in our bodies when cells mutate – a natural selection against cancer known as immunosurveillance.
So how come there is cancer at all?
The interaction between tumour and immune system is referred to as 3E model. First you have the Elimination phase, in which the immune cells kill immunogenic cancer cells. But not all cancer cells carry the same mutations. This means a selection of cancer cells with non-immunogenic mutations occurs and the tumour (or at least part of it) persists. During this Equilibrium phase the tumour is under the control of the immune system: it does not increase in size and has no immediate negative effects on the health of the person.
However in the end stands the Escape of the cancer cells. Not only do the escaped cells not express immunogenic antigens, they also develop mechanisms to suppress the immune system. They produce anti-inflammatory messenger molecules (=cytokines) that deactivate immune cells. Similarly tumour cells can express molecules on their surface that can interact with molecules on the surface of immune cells and deactivate them that way.
This deactivation of immune cells is what immunotherapy tries to block. CTLA4 and PD-1 are inhibitory molecules found on the surface of T cells (a type of immune cell). Tumour cells can express the ligands, molecules that can bind CTLA4 and PD-1 (CD80/CD86 and PDL1/PDL2) and thereby deactivate T cells that attack the tumour. In the new therapy approach, patients are given blocking antibodies for the CTLA4 or PD-1. Antibodies are small molecules produced by B cells, which can recognise very specific structures. They do not deactivate T cells but block the receptor so the tumour cells cannot deactivate the T cells. With this approach more activated T cells are present in the tumour and kill tumour cells.
And indeed the approach has been a huge success. In 2010, a two-year clinical trial using an anti-CTLA4 antibody was the first life-extending treatment for advance melanoma (skin cancer)! In 2011 ipilimumab (an anti-CTLA4 antibody) was approved for treatment of metastatic melanoma. These first successes earned immunotherapy the title science breakthrough of the year in 2013. The PD-1- blocking antibodies Pembrolizumab and Nivolumab were approved for advanced melanoma in late 2014, while clinical trials for other cancer types such as lung cancer are ongoing.
Future of Immunotherapy
Unfortunately, at this point in time, Immunotherapy will not be the universal cure for cancer. The therapy does not work in all cancer types. So far skin and lung cancer have shown good success rates, while colorectal cancer has been less susceptible for the antibody treatment.
As a new treatment approach, immunotherapy is only given to patients in whom all other treatment options such as chemotherapy, radiation or operation failed or are not an option. Given the success, antibodies will move up in the treatment plans and will be given to patients with earlier stages of cancer in the future. But not all patients respond to the new therapy – depending on cancer type and antibody given only about 20-50% of patients demonstrate an effect on tumour size. So far we do not understand what factors determine if a patient will respond or not.
Ideally we would be able to find so-called biomarkers, easily measurable factors that can tell us if a patient will respond to a treatment or not. That way we could design individual treatment plans for each patient, giving priority to the most promising medication. The obvious candidate for a biomarker is the expression of the CTLA4 and PD-1 ligands on the tumour cells as these deactivate the T cells – but so far no correlation could be found. Two studies in 2014, identified PD-1 and PDL1 levels on immune cells as well as the number of T cells within the tumour as possible biomarkers. Interestingly, the complexity of antigens that can be recognised by the T cells in the tumour also correlate with therapy success. This means that a tumour with more mutations and therefore more possible immunogenic antigens is more likely to be killed by T cells once the T cell inhibitors are blocks. More work is ongoing and needed before Immunotherapy can move into early cancer patients.
You might already wonder about side effects when you unhinge the immune system. And you are right, as CTLA4 and PD1 are expressed on all T cells, also outside of the tumour, the treatment affects the immune response in the whole body which led to autoimmunity in early drug trials. The now approved medications are reported to have few side effects.
Other forms of Immunotherapy
Rather than using antibodies to activate immune cells, antibodies can also be used to target tumour cells for disposable. One example for this are antibodies against CD20 (e.g. Rituximab, Tositumomab), which target immature B cells and are used in lymphoma patients who suffer from extended B cell proliferation. Antibodies do not kill the targeted cells directly – but they can mediate the killing. You can imagine antibodies like tags – they signal for example macrophages that this cell should be killed.
Antibodies can also be linked to toxic or radioactive molecules. That way cancer cell can be targeted without negative effects on the surrounding healthy tissue.
The problem with this approach is that tumour specific antigens need to be known so they can be targeted. Unfortunately such targets are not known for most tumours or can be widely different within the same cancer type in different patients. Large studies are therefore ongoing to identify immunogenic antigens for different tumours.
Besides these antibodies based approaches, transfer of immune cells as therapy is also being investigated. One idea is to isolate T cells from the tumour tissue, expand them in the lab and reinfuse a high number of tumour specific T cells into the patient. This strategy has worked, but is limited by the accessibility of tumour tissue.
In a different approach (chimeric antigen receptor therapy), T cells are isolated from the blood, modified in the lab and then reinfused. In this personalised approach T cells are genetically modified to express receptors that recognise the tumour antigens and activate the T cells. While this approach uses an easily accessible source of T cells, the large effort needed to modify the cells makes it very expensive. Nonetheless the therapy had good success in first clinical trials, with 50% of patients responding. More trials are ongoing.
With these encouraging results on so many different ideas, I hope you enjoyed this overview. If you want to know more about any part just let us know.