Fog clearing above the mountains

The target hunters

Meet the scientists exploring new immunotherapy pathways in the battle against cancer

“When you are right at the precipice, it’s like you are squinting through fog, trying to understand what is in front of you. There is nothing quite like that feeling of discovering something new.”

Dr Robert Johnston’s passion for science started with school science fairs while growing up in California. Over the years, this passion grew, eventually leading him to his current role as a Senior Scientist in the Oncology Biomarker Development team at Genentech Research and Early Development (gRED, part of Roche).

“There is an incredible rush when you have that ‘lightbulb’ moment,” he explains. “When you realise you have discovered something new and fundamental. To share that with the scientific community is wonderful. But then to be able to translate that knowledge into a benefit for patients suffering from terrible diseases, that is truly inspiring.”

Photo of Dr Robert Johnston
Dr Robert Johnston, Senior Scientist, Oncology Biomarker Development, gRED, a member of the Roche group

One such ‘lightbulb’ moment came for Robert as a post-doctoral research fellow in gRED back in 2012. He was one of a small team of scientists led by Jane Grogan, including Xin Yu, Eugene Chiang, and Karl Banta, investigating molecules and cell signalling pathways involved in autoimmune conditions like asthma, lupus and rheumatoid arthritis. Their work focused on a receptor called TIGIT (also called T-cell immuno-receptor with Ig and ITIM domains) that had first been identified by gRED scientists in 2002.1 They noticed that it seemed to be playing a role in regulating immune system responses.2 When they began to look more deeply at TIGIT, they spotted something interesting – TIGIT was highly expressed on a certain type of immune cell, called a CD8+ T-cell.

When immunology meets oncology

“That really got us thinking,” recalls Robert. “As this is a type of T-cell that we knew played a key role in the immune response to cancer. But we weren’t an oncology lab. We were in the immunology department. We were in need of a helping hand.”

That helping hand came from Dr Ira Mellman, Vice President of Cancer Immunology, gRED, and his team, based just down the hallway from the lab Robert was working in. Ira’s team was at the cutting edge of cancer research and, as it happens, experts in what was still a fairly new concept – cancer immunology.

10 years ago, this was all new. No one was looking at the role of the immune system in cancer – we were some of the first to go there,” recalls Ira. “As it turns out, the idea was transformational.”

Our immune system is designed to spot and kill anything ‘foreign’ that shouldn’t be in our bodies – including viruses, bacteria, and even cancer cells. The subtle changes that occur in cancer cells, called mutations, mark them out as being different to normal cells. These changes signpost to immune cells, including T-cells, that they should be destroyed. But in some cases, mutated cancer cells are able to evade the immune response and multiply, causing harm. Cancer immunotherapies are drugs that help the immune system to be better at spotting and killing cancer cells.

In other words, cancer immunotherapy aims to harness the power of the immune system to fight cancer.

Like brakes in a car

PD-L1 was one of the early cancer immunotherapy targets that Ira and his team were interested in, and it quickly became apparent that there were similarities between TIGIT and PD-L1 in terms of the part they play in the immune response to cancer.

TIGIT and PD-L1 both act like brakes in a car, putting a halt to the body’s natural immune responses. Under normal circumstances, this negative regulation of the immune system is a good thing, designed to stop immune cells from overreacting to a foreign threat, like a virus, and inadvertently causing damage to healthy cells – like a runaway car with broken brakes.

However, some cancers make the most of this protective feedback loop, signalling via negative regulators like TIGIT and PD-L1 so that cancer cells can multiply and grow, unchecked. The theory is that by designing new drugs that block TIGIT, and combining them with the pre-existing drugs that block PD-L1, you remove the brakes and allow the immune response to kick in, with T-cells engaging and killing cancer cells.

What appears to be special about TIGIT is that blocking it doesn’t just remove the brakes on immune cells, it actually accelerates their activity, amplifying the immune response. How? Blocking TIGIT seems to allow a second pathway to kick in, involving a protein called CD226, which acts like the accelerator on the car, speeding up the immune response.

I’ll never forget that first experiment.

“When we blocked TIGIT and PD-L1 in cancer, we seemed to synergistically enhance the immune-mediated killing of cancer cells. The results were well beyond our expectations,” says Robert. “In a matter of weeks, the entire lab moved into the cancer immunology department. The data just demanded that we make that leap.”

From bench to bedside, and back again

They published their findings on TIGIT to a flurry of interest and excitement in academic circles.3 Since then, hundreds of papers have been published from labs all across the globe on TIGIT, and multiple anti-TIGIT drugs are now in development, in the hope that by blocking this pathway it may be possible to activate the immune system against cancer. Some of those drugs have shown promising early outcomes in cancer patients, and are entering phase II and phase III clinical trials.

Traditionally, research groups discover a target, make a molecule for the target, and then hand it over to the clinicians before moving on to the next project, with discoveries going from laboratory bench to patient bedside. But that’s not the case for Ira’s team.

Photo of Dr Ira Mellman
Dr Ira Mellman, Vice President of Cancer Immunology, gRED, a member of the Roche group

“We don't work that way,” explains Ira. “When a drug goes into the clinic – that's when things really get going, because you see how patients respond and you spot things that are surprising from a scientific perspective.”

Ira and his team take these insights from the bedside and feed them back to the bench, helping them to understand how these targets work – something that he says is critical to avoid years spent “barking up the wrong tree” in the hunt for the next potential target. Ultimately, their aim is to find the next immunotherapy treatment that can work with the body to fight cancer.

The hunt continues

“Those of us in Cancer Immunology believe that by learning from our patients, a process I like to call clinical discovery, we stand the best chance of finding the next immunotherapy arrow to add to our quiver,” Ira says. “Clinical discovery provides an exciting opportunity to reveal basic scientific principles, but more importantly, it is the most direct path to make a difference, to do something useful for patients. That’s what drives us forward.”

Now part of gRED’s reverse translation team, Robert also spends his days spotting trends and searching for potential drug targets in huge banks of patient data.

For many researchers it’s rare to work on even one new drug target that makes it through to clinical trials. So, looking back, how does Robert feel about the experience of working on TIGIT?

It still gives me shivers. When I started working on TIGIT, we were working in test tubes, we weren't even thinking about cancer. Now, not even 10 years later, to see multiple drugs being developed, and to begin to see the potential benefits this could have for patients... it’s incredibly gratifying and humbling.

References

  1. Abbas AR, Baldwin D, Ma Y et al. Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immunol. 2005 Jun;6(4):319-31. doi: 10.1038/sj.gene.6364173.
  2. Yu X, Harden K, C Gonzalez L et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol. 2009 Jan;10(1):48-57. doi: 10.1038/ni.1674.
  3. Johnston RJ, Comps-Agrar L, Hackney J et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014;26(6):923-937. doi:10.1016/j.ccell.2014.10.018.

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Tags: Science, Oncology