The scientific community has made great strides in the understanding and treatment of cancer, with survival rates improving significantly for many diseases. Our knowledge of tumours and how they interact with the immune system is increasing all of the time, however, the more we learn, the more questions arise. This is the challenge facing cancer researchers everywhere, including those at Roche.
Our immune system helps protect us from infections, allowing us to live healthy lives. Scientists are exploring ways to enhance the immune system so it can fight cancer, as well as infections. They are also extending their understanding of cancer immunology to pursue new and innovative targets. “Our task at Roche is to find ways to help not only our immune system fight infections, but enhance it so that it can also fight cancer,” explains Ira Mellman, PhD, Vice President of Cancer Immunology at Roche. “Our research has given us the understanding and opportunity to do exactly that.” Recent research into cancer immunotherapy and human immune biology has led to two innovative approaches to treating cancer from the Roche research and development teams.
“One of these exciting approaches is the ability to understand how best to separate out all of human cancers into just three immune profiles.” said Dr Ira Mellman PhD, Vice President of Cancer Immunology at Roche. By understanding the immune profile, it is thought that it will be possible to be very specific with each treatment approach. “The second is the cancer immunity cycle, a framework that Dr Daniel Chen and I devised, which helps to describe how a tumour interacts with the human immune system.”
Roche scientists believe all human cancers can be grouped into three immune profiles, depending on their immune status – called immune phenotypes. These immune profiles have been termed ‘immune deserts’, ‘immune-excluded tumours’ and ‘inflamed tumours’.
“When thinking about these phenotypes, we like to think of an army of immune cells, also known as T Cells,” said Dr Mellman.1
The immune desert is exactly how it sounds. There is a tumour, but no T Cell army is present to mount an attack. There is a total lack of an immune response present in the tumour.
You can imagine the T Cell army is ready to attack but is unable to scale the walls or cross the moat of the castle in order to attack effectively. This means that there is an immune response but the T Cells do not seem to be able to penetrate into the tumour castle grounds, known as the tumour micro environment.
When the tumour is inflamed it has an army of T Cells armed and ready to attack the cancer from inside the castle grounds. While there is an active immune response that can be seen within the tumour, there may still be inhibitory factors preventing that active immune response from actually destroying all of the cancer cells. This is seen in cancers such as melanoma, lung and bladder.
Having the knowledge of these three immune phenotypes allows the application of different treatment strategies to target the individual immune biology, ensuring that an individual has the best chance of a response to a specific treatment.
The cancer immunity cycle is a framework that helps to describe how a tumour interacts with the human immune system. Each of the seven steps within the cycle can be grouped into one of the three immune phenotypes, as shown in the illustration below. The cycle framework was devised and produced by Dr Dan Chen and Dr Ira Mellman and was first published in a pivotal article in the journal Immunity in 2013.2
The cycle starts with antigen release. This is the process by which cancer cells die and consequently release antigens. Essentially, antigens are protein bits of the cancer cells that have died.
The next step in the process is antigen presentation. This is where the protein bits (antigens) can get picked up by antigen-presenting cells, which then take them to local draining lymph nodes. An example of an antigen-presenting cell is a dendritic cell.
At step 3, the antigen-presenting cells are able to present the protein bits (antigens) to T cells, which are present because of nearby cancer cells. Importantly, this series of events only take place when the immune system is working correctly and is able to fight cancer.
An example of this step in practice is the OX40 pathway, which is one way that the immune system interacts with cancer. In this instance, the OX40 molecule binds to OX40 receptors on T cells (priming) and subsequently the T cells are activated by the tumour.
By stimulating the OX40 pathway it is thought to increase the anti-tumour effect that OX40 has in the tumour microenvironment.
Now that the T cells have been activated in step 3, they enter the bloodstream and travel around the body looking for tumour cells.
When the T cells have arrived at a location where tumour cells are present, their job is to infiltrate the tumour. Infiltration of the tumour means to leave the blood vessel and enter into the tumour microenvironment. Essentially the T cells break down the tumour wall and force their way in.
Now the T cells are in the tumour microenvironment. At this step, the T cells become able to specifically recognise tumour cells
Here, another pathway – that informs how the immune system interacts with cancer – comes into play. This pathway is called the CEA/CD3 pathway. It allows T cells and tumour cells to interact with one another by binding a protein called CD3, expressed by T cells, and another protein called CEA, expressed by tumour cells. This enables the T cells to specifically recognise the cancer.
It is also thought that CEA/CD3 activity correlates with CEA expression level, showing higher potency against tumour cells with high expression of CEA.
The last step in the cycle is T cell killing. Here the T cells are activated against the tumour cells and are able to kill them. This important step is where an activated T cell has recognised a cancer cell and now actually kills it.
Yet, within the immune system there are many inhibitory factors that make it impossible for the T cell to kill the cancer cells. Two examples of these inhibitory factors are TIGIT and PD-L1.
TIGIT is normally found on T cells alongside another protein called CD226 and binds to a protein on tumours and tumour-infiltrating immune cells called poliovirus receptor (PVR). This allows the T cells to kill the tumour. TIGIT can, however, also inhibit CD226 and preferentially bind to PVR instead. By pushing CD226 out of the way, TIGIT can prevent T cells from killing cancer cells.
PD-L1 can be expressed in the tumour microenvironment across a range of different types of human cancer, including bladder, lung and triple-negative breast. PD-L1 interacts with PD-1 and B7.1, both found on the surface of T cells, causing inhibition of T cells and thus, the T cells are not able to effectively detect, attack and kill tumour cells.
Imagine a patient has presented with a tumour that demonstrates characteristics of an immune desert. In this scenario, there is no pre-existing immune response. Therefore, the patient may best respond to a treatment that will help this patient to generate an active immune response. Consequently, a treatment that acts at step 1 (antigen release), 2 (antigen presentation) or 3 (priming and activation) of the cancer immunity cycle would be best suited.
What the cancer immunity cycle shows is that there is more than one way to harness the power of the immune system; it may be possible to achieve similar results using different biological tools. At present, Roche scientists are targeting various steps in the cancer immunity cycle, as demonstrated in the growing cancer immunotherapy pipeline. By targeting multiple steps in the cycle, Roche scientists are taking a comprehensive approach to cancer immunotherapy, and are evaluating which combinations of approaches may best recruit the immune system to attack specific cancers.
Taking advantage of multiple ways to harness the power of our immune systems could be the future of cancer immunotherapy. With their commitment to, and ever increasing knowledge of immune biology, Roche scientists aim to continue to shape the future of oncology treatment.
Ira Mellman and Dan Chen are two of Roche’s most prominent scientists who have dedicated their lives to the pursuit of knowledge in the field of oncology. Today, both are leading authorities in cancer treatment and cancer immunotherapy.
Ira Mellman, PhD – Vice President, Cancer Immunology, Roche – is a scientist, a member of the National Academy of Sciences and former Yale Professor.
Dan Chen, MD, PhD – Vice President, Global Head of Cancer Immunotherapy Development, Roche – is an oncologist and former Howard Hughes Medical Institute Associate who ran the Stanford University Cancer Center’s metastatic melanoma clinic.
Groopman, The New Yorker, 2012
Chen, D and Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013; 39(1): 1-10