Promising developments in antigen and immunotherapy. 

Written by:
Dr Rebecca Case-Upton BSc (Hons), PhD 
Kidney Cancer UK Medical Publications.
There were many exciting headlines in the newspapers recently: “Scientists claim cure for cancer is closer”, “Cure for cancer ‘two years away’ after British scientists DNA breakthrough”. The research supporting these headlines is very promising and is likely to positively impact kidney cancer treatment in the near future.  However, it is important to inform people that getting research into the clinic can take time and we are therefore taking the opportunity to demystify the research by explaining what has happened and how it may affect future kidney cancer treatments.
Previous promise of immunotherapy
Prior to this new research, immunotherapy has been looking promising in the battle against cancer. The body’s immune system acts to destroy cells which are not ‘normal’, such as cancer cells which have many DNA mutations; which make them multiply out of control, grow their own blood vessels and behave irregularly. So it makes sense for us to work with our own natural ways of destroying cancer cells as a method of cancer treatment. However, how cancer cells evade and overwhelm our own immune system still requires more research. Major advancements in our understanding of this area have been made with this recent research.
The new research
The research, conducted by two groups working together, was published on the March 3, 2016 in the journal Science. Professor Charlie Swanton, a leading expert on genetic changes and mutations in tumours, is based at the Francis Crick Institute and Dr Sergio Quezada, based at University College London, is an expert in how the immune system interacts with tumour cells. Together their research has uncovered missing details about how specific antigens on the tumour surface play a role in a tumours’ destruction by the immune system and how it responds to immunotherapies.
Scientific concepts that help our understanding of the new research
Before explaining more, let’s revisit knowledge about tumours and antigens, which has previously been discovered but is vital to understanding the potential of this new research:

• Over the past few years it has become apparent that tumours are not just masses of identically mutated cells: there are differences in the mutations and cells within a tumour. This is known as heterogeneity. As with animal evolution where different species branch off from common ancestors, within a tumour, cancers evolve into genetically-mutated and different cells, like a branch of a tree. Even if your immune system destroys some cells, others which differ can be left behind and then multiply again after treatment. The same has been shown to happen in kidney tumours. Within the same kidney tumour the cells differ genetically, Gerlinger et al, 2012.
• Antigens are proteins which are displayed like flags on a cells surface. Antigens are the ‘flags’ that immune cells look for when monitoring whether a cell is ‘normal’/healthy or not. If an immune cell doesn’t recognise the antigen as healthy or normal, then it will destroy the cell. When each genetic change occurs in a cell, such as a DNA mutation, a different antigen is expressed on the surface of the cell. Previously it has not been known if it matters if the immune system recognises a specific antigen, or whether cells will be destroyed if any abnormal antigen activates the immune cell.
• Cancers have a defence mechanism. They are able to release a substance called PD-L1 which activates PD receptors on immune cells and dampens down their response to destroy tumours cells. This mechanism can be modified using drugs such as nivolumab (Opdivo), which is a monoclonal antibody that blocks the PD-1 receptor and lifts the cancer driven dampening of the immune system. Nivolumab is currently being reviewed by NICE for use in kidney cancer after impressive results in a clinical trial and is already in use in the USA (Motzer et al, 2015).

The next steps taken by the latest research and the potential it holds
The new research puts this all together and has shown there is a link between mutation heterogeneity and the antigens shown on the surface of the different cells. People with greater diversity in their tumour often do not survive as long and respond to treatment as well as people with more simple tumours. The immune system finds it more difficult to attack cells with a more diverse range of mutations (and antigens). However, it was shown that like animal evolution it is possible to trace tumour evolution back to the original DNA mutations, which all the diverse tumour cells originate from. From this there were common antigens displayed from these original mutational changes. These antigens were shared by all of the cancer cells in the tumour. By isolating immune cells which identify these shared antigens, the immune cells should be able to destroy all of the cells in the tumour. The potential treatment could come in a form where immune cells are harvested that respond to a patients shared antigen (displayed when the original DNA mutations occurred), these cells could then be multiplied in a lab and reintroduced into the patient’s body in quantities which will be effective to destroy all of the tumours within their body. The antigen ‘flags’ on the cell surface, that the DNA mutations leave behind, have been described as the cancers “Achilles heel” and the way in which they can be attacked.
The new research may also provide information on why immunotherapy treatments work in some people and not others. In the study it was shown that tumours that had less antigen diversity, which the immune system would have found easier to attack, also produced greater levels of PD-L1, the substance which dampens down the immune system. Those with lots of shared antigens responded well to immunotherapy with a drug called pembrolizumab (Keytruda, which blocks PD-1 receptors in a similar way to nivolumab). So by looking at how diverse people’s antigens are, may aid effective and personalised use of immunotherapies. This may be the most immediate benefit of this new research. This is very promising for kidney cancer which has been shown to respond to nivolumab in a Bristol Myers Squibb clinical trial. Looking into a patients antigen profile may allow clinicians an insight into how beneficial treatment with this drug might be, potentially avoiding unwanted side- effects.
What this means for people with kidney cancer
Overall, this study looks very promising and provides new ways to attack tumours. The scientists involved are very confident that this will lead to new treatments that will prove effective for all stages of cancer disease. However, it is very important to stress that there will be many layers of research before everyone is receiving a personalised immune cell therapy. Tumours in different organs will need to be analysed to see if they show shared antigens. The research was conducted in lung and melanoma tumours but has yet to be proven in kidney tumours and many other types of tumour across the body. However, it still remains likely that this theory will be consistent across all tumour types. This work will need to be conducted, along with comprehensive clinical studies and NICE approval before a technology or treatment is released. This all takes time and there may be delays in research for less common cancers. So there are exciting times ahead in cancer research and we really hope that the scientists’ claims that there should be “treatments available in two years’ time” come true. Let us hope and make sure that the research in this area is conducted in kidney cancer as quickly as possible and that shared antigens are shown in kidney cancer.
References
R.J. Motzer et al, Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma N Engl J Med 2015; 373:1803-1813
M. Gerlinger et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012 Mar 8;366(10):883-92.