Picking more needles out of the haystack - new method refines ways to pinpoint cancer

Beware, cancer! Thanks to a newly developed technology we are gaining insights into how immune cells can spot cancer cells that try to play hide and seek. This achievement is an important step in making anti-tumour immunotherapy more precise.

In 10 seconds? Antigens, the chemical ‘signals’ displayed on the surfaces of all the cells of our body, help the immune system to distinguish friend from foe. A new method sifts through a huge number of antigens and flags up those that can provoke an immune response that allows our natural self-defence system to deal with tumours. (Read the science)

T cells are the soldiers of the immune system

What is the finding? T cells, soldiers of our immune system, are able to recognize and fight tumours, but only if they are able to sense a certain type of chemical signal, called an antigen, that informs a T cell to attack. So, it is important to find antigens needed to allow them to recognise the enemy. We have developed a new way to identify antigens that can elicit a T cell reaction. It works by scanning through massive numbers of potentially existing antigens to find the ones that actually do cause response from T cells. This new technology is enabling for scientists who are looking to develop new T cell-based medicines. (Read the paper)

How was the method developed? We took advantage of a key feature of T cells: their ability to target infected or mutated cells with a toxic molecule called granzyme B in an extraordinarily focused way. When a T cell decides to kill a target cell, it delivers granzyme B only to the target without allowing any of it to enter surrounding healthy cells. Using this natural feature, we developed a method to isolate cells marked for destruction. These targets are identified by fluorescence-activated cell sorting, or FACS, and the antigens they carry are revealed by DNA sequencing. Knowing the antigens are at the heart of the interactions between T cells and tumour cells is important because it then allows researchers to appropriately stimulate the right T cells to treat cancer with. (Read more about classical methods)

What do T cells do? They are a specialized type of immune cells, on constant patrol around the body, looking out for foreign invaders or cells that have gone rogue and could form tumours. T cells do this job by inspecting different antigens, which exist on the surface of every cell in the body, using unique proteins of their own called T cell receptors (TCRs). Antigens signal to T cells whether the host cell being inspected represent normal “self” tissues or have become “non-self” – that is, are infected by foreign pathogens or harbor harmful cancer mutations. If a foreign or mutated antigen is discovered by a T cell, it initiates a response that is aimed at clearing out the offending antigen-bearing target. (Read about a way T cells discover antigens) 

Is it that simple? Unfortunately, no. The molecular interactions by which T cells interact with antigens are very complex. So, decoding the identities of the antigens that trigger their responses has been a major challenge in understanding the role of immunity in disease. However, the potential payoff of being able to speak the language of T cells is enormous. For example, it would give scientists the ability to engineer or otherwise direct T cells against known tumour antigens, providing a powerful means to perform precision cancer therapy. (Read more)

So, why is this better than what we’ve had before? The innovation of this approach is that very large sets of candidate antigens can be simultaneously tested in parallel. In fact, we can test up to a thousand times more candidate antigens than any other current method can handle. Thus, we are getting a better insight into how to make safer, more effective cancer immunotherapies. (More on T cell recognition patterns) 

What does it mean for the future? This is a key step forward because it increases our ability to find T cells that will fight tumours and that could be used in therapeutic cell products. Cancer immunotherapy is based on enabling T cells to go to war against tumours – and it has shown some promising results to-date – but it doesn’t work for everyone at the moment. New antigen targets are needed so that new therapies can be designed that can help a larger chunk of the patient population. (Read why immunotherapy merited the Nobel Prize in Medicine in 2018)

What we have now: T cell therapy can yield results but it has its limits

As summer turned to autumn last year in America, one woman received the perfect gift: she was told that her cancer had completely cleared up.

The 66-old lady from Ohio was a long sufferer of Non-Hodgkin Lymphoma and underwent CAR T cell therapy as part of a clinical trial. A month later she was given the all-clear.

She benefited from a relatively new therapy where T cells are removed from a sample of the patient's blood and modified in the lab by inserting a gene for an immune receptor that can redirect the reactivity of the T cells towards the tumor. Technicians then grow these cells until there are billions of them and re-infuse them back into the patient.

In the miraculous case above, the patient received a type of synthetic immune receptor called a chimeric antigen receptor (or CARs). But many other types of immune receptors could be used to guide cell therapies, including naturally occurring T cell receptors (TCRs) like the ones that already exist inside of every person!

A key advantage of using TCRs to guide cell therapies is that these receptors can “see” many more potential targets, including those that exist inside of a cell, than CARs, which are restricted to only seeing targets that naturally occur on the outer surface of a cell.

We hope to see TCR-based cell therapies continue on the path blazed by CAR-T therapy to create a new class of treatment options to help a whole new generation of cancer patients.

(Psst, Govinda distilled 9 research papers to save you 803.6 min)

Dr Govinda Sharma

by Dr Govinda Sharma

Post-Doctoral Fellow at Canada's Michael Smith Genome Sciences Centre, researching novel methods for high-throughput, function-based T-cell antigen screening. Govinda is currently in the process of forming a biotech company to use the technology described in this digest pave the way for immune cell therapies in cancer.