“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.”

Many scientists spend most of their careers in labs, doggedly pursuing pathways that may or may not lead to a discovery. Robert Johnston spent many years on the bench following his curiosity. His passion for science started with school science fairs while growing up in California and led to Genentech, where he is now Senior Scientist in the Oncology Biomarker Development team at Genentech Research and Early Development (gRED).

When Robert was a post-doctoral research fellow in gRED in 2012, he was part of a small team of scientists led by Jane Grogan – including Xin Yu, Eugene Chiang, and Karl Banta – who were investigating molecules and cell signaling 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 Genentech scientists in 2002, who noticed that it seemed to play a role in regulating immune system responses. 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.

That type of T-cell, Robert knew, plays a key role in the immune response to cancer. “That got us thinking,” he said. “But we weren’t an oncology lab. We were in the immunology department. We were in need of a helping hand.”

Immunology meets oncology

That helping hand came from Ira Mellman, Vice President of Cancer Immunology, gRED, and his team, who were based just down the hallway from the lab where Robert was working. Ira’s team were experts in what was still a fairly new concept – cancer immunology, which aims to harness the power of the immune system to fight cancer.

“Ten 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 medicines that help the immune system to be better at spotting and killing cancer cells.

One of the early cancer immunotherapy targets that Ira and his team were interested in was called PD-L1, and when Robert and Ira compared notes, it quickly became apparent that there were similarities between TIGIT and PD-L1 in terms of the roles they play in the immune response to cancer.

The lightbulb moment

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.

But some cancers make the most of this protective feedback loop, signaling via negative regulators like TIGIT and PD-L1 so that cancer cells can multiply and grow, unchecked. The scientists theorized that if they could design new medicines that block TIGIT, and combine them with the pre-existing medicines that block PD-L1, it would be possible to remove the brakes and allow the immune response to kick in, with T-cells engaging and killing cancer cells.

What’s more, TIGIT doesn’t just remove the brakes on immune cells, it actually accelerates their activity. Blocking TIGIT seems to allow a second pathway to kick in, involving a protein called CD226, which acts like the accelerator on the car, amplifying 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.”

This was a moment he had worked toward and waited for his entire career. “There is an incredible rush when you have that ‘lightbulb’ moment – when you realize you have discovered something new and fundamental,” he says. “To share that with the scientific community is wonderful. But then to be able to translate that knowledge into something that might help patients one day, that is truly inspiring.”

From bench to bedside, and back again

The scientists published their findings on TIGIT to a flurry of interest and excitement in academic circles. 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 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.

“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 better understand how these targets work.

The hunt continues

Genentech continues to explore different technologies and classes of medicine, such as bispecific antibodies, to engage with novel targets like TIGIT to pursue the next frontier of cancer immunotherapy.

“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.

“It still gives me shivers,” Robert says, recalling the discovery. “When I started working on TIGIT, we were working in test tubes; we weren't even thinking about cancer.” Just 10 years later, he’s able to see his work develop into multiple treatments that could potentially bring the benefits of immunotherapies to more patients. “It’s incredibly gratifying and humbling."