The Hunt for New Checkpoint Inhibitors

Drugs that release the brakes on immune cells have helped many cancer patients, but not enough. Amgen is using human genetics and cutting-edge biology to search for new checkpoint targets that will work in more types of cancer and more patients.

Flavius Martin

Immunotherapy is the art of taking the power of the immune system and diverting it to kill cancer cells. Up to about, you know, 20 years ago, the word cure was almost forbidden in the oncology dictionary if you wish. And in the last 10 years this particular armamentarium of immunotherapy is giving us hope.

Ray Deshaies

However, it’s still a minority of cancers in which we’re seeing immunotherapy work. We’ve made impressive progress, but you know there’s much greater distance yet to go.

Amgen has really been an innovator in the area of immunotherapy with our BiTE molecules. And we have now a whole portfolio of BiTE molecules that we’re advancing through clinical studies. But in addition to that, we have a whole other approach trying to identify novel checkpoint molecules that are governing the immune response to cancer.

So immune cells have both gas pedals and brakes that control their function. And the brakes, in particular, prevent the immune cells from attacking our own tissues—and cancer, of course, arises from our own tissues.

One of these brakes is known as CTLA4, and what’s fascinating is one of the current checkpoint drugs attacks the CTLA4 protein. Now we know from human genetics that people with mutations in CTLA4 have a predisposition to get autoimmune diseases.

Wenjun Ouyang

So in autoimmunity, the immune system become hyperreactive. Immune cells like T cells start attacking your own tissue. If we can identify those pathways, we actually can redirect the immune cells to attack cancer. So we actually now explore human genetics to try to identify pathways.

Ray Deshaies

And so we turned to our colleagues at deCODE Genetics, and we asked them, Gee can you identify for us regions in the genome that contain genes that predispose to autoimmune diseases, say like rheumatoid arthritis. And they said sure, and they gave us a list of genomic regions. And Wenjun Ouyang went hunting in those genomic neighborhoods, and he came up with some candidate genes that he thought might be responsible for this effect that deCODE was seeing.

Wenjun Ouyang

So identifying a gene or pathway through human genetics is just really the first step of innovation, right? Because a lot of time, we don’t know the function of that gene or that pathway.

Ray Deshaies

We don’t know where that protein is in the cell, we don’t know what that protein does. These are all things we need to figure out.

Flavius Martin

In the last five years we witnessed a revolution in the technology tools that we have now available to study biology.

This revolution includes tools like CRISPR which allows us to edit in and out very efficiently genes into cells. It includes viral vectors which we can put into cells and regulate genes up or down at will.

Ray Deshaies

We do single cell RNA seq on all these immune cells in a tumor to identify the genes that they are expressing. And if we find something that looks like a brake being expressed in those cells, then we can make a medicine that targets that brake to essentially release it. And so that’s another approach that Wenjun is taking that’s looking very, very promising.

Wenjun Ouyang

By closely working with deCODE, we are working on some very novel genes and novel pathways. So therefore being able to perform this cutting-edge science and thinking about every day how we can translate this novel mechanism and pathways into immunotherapy is exciting everyone on my team.

Ray Deshaies

It’s perhaps ironic, but when I came to Amgen, I was expecting that I was going to be, you know, the disruptive influence, coming from academia. And what I found very quickly was I was actually more conservative than my coworkers, and I was shocked at the audacity of what people were trying to do.

We can’t solve these problems by incrementalism, and it’s going to take bold, visionary strokes.

Three years ago, I lost my brother to cancer. He actually entered a phase 1 clinical trial for one of the therapies that’s now on the market, and he didn’t respond.

So when I look at the work that we’re talking about today, we can potentially save thousands and thousands of other people’s brothers and uncles and sisters and mothers and daughters and sons over the next generation. That’s a very powerful feeling.

In the quest to make cancer a curable disease, a lot is riding on advances in the field of immuno-oncology. Medicines that spur an immune attack against tumor cells are helping patients to live longer and even become disease-free in some cases.

“Up to about 20 years ago, the word cure was almost forbidden in oncology,” said Flavius Martin, vice president for Oncology Research at Amgen. “In the last 10 years, immunotherapy has given us hope.”

Extending that hope to more patients has become a major focus of cancer research. “We still have a long way to go,” said Ray Deshaies, Amgen’s senior vice president for Research. “So far, immunotherapy only works in a minority of cancers. Even in those cancers where it does work, you typically see a striking remission in only about one-third of the patients treated. But I’m very optimistic about the future and in particular about the work that Amgen is doing now.”

Releasing the brakes on immune cells

That work includes an ambitious drug discovery program aimed at leveraging human genetics to find entirely new immune checkpoint inhibitors. These checkpoints are the body’s way of ensuring that our defensive cells are only deployed in response to genuine threats.

Ray Deshaies, Senior VP, Research

“Immune cells have gas pedals and they have brakes,” Deshaies explained. “The brakes prevent the immune cells from attacking our own tissues. Since cancer arises from our own tissues, those brakes prevent our immune cells from attacking cancer.”

Drugs that release the brakes can send dormant T cells into attack mode, but the options for treating patients with this strategy are still limited. First-generation checkpoint drugs are directed against just two pathways—CTLA-4 and the PD-1/PD-L1 axis. The universe of potential checkpoint targets is much larger, but identifying truly promising research leads has been difficult.

“The big challenge is that there are thousands of genes that regulate immune cells, so it’s hard to find the relative handful of genes that could lead to great medicines,” Martin said.

“Every week, we see new scientific papers and new claims about immune genes that may be important in cancer,” said Wenjun Ouyang, executive director, Research. “Most of them are probably irrelevant in terms of drug discovery. The real question is, What are the dominant mechanisms? Where are the breakthroughs that will evolve into the next PD1 or CTLA4 inhibitors?”

“Identifying an interesting gene is really just the first step in innovation. A lot of the time, the genetics points to a gene about which very little is known. What is the gene’s function? What type of protein does it make?"
Wenjun Ouyang

Finding new leads in autoimmune disease

It’s a question that Amgen is better positioned to answer than most companies thanks to its deCODE Genetics subsidiary in Iceland. “One of the major reasons I decided to come to Amgen was to look into the genetics coming from deCODE,” Wenjun said. “I think it’s one of the most innovative approaches being used now in drug discovery.”

In the hunt for new checkpoint targets, genes linked to autoimmune disease may provide the best starting point. Conditions like rheumatoid arthritis happen when immune cells fail to apply the brakes that normally stop them from harming healthy tissue. The same genes that make immune cells too aggressive in these disorders might be repurposed to prompt immune attacks against tumors. Validation for this hypothesis comes from CTLA4, a gene implicated in autoimmune conditions like type 1 diabetes and the target for the first approved checkpoint inhibitor.

“With the precedent of CTLA4 in mind, we approached our colleagues at deCODE,” Deshaies said. “They gave us a list of genomic regions with variants that influence autoimmune disease, and Wenjun and his team went hunting in those regions. Through experiments, they’ve identified some new genes that look like they regulate autoimmunity. And by modulating the function of these genes, we believe we’ll be able to predispose the immune system to attack cancer.”

Wenjun Ouyang, executive director, Research

Tackling novel biology

Applying human genetics to drug discovery sounds straightforward, but it actually poses challenges beyond the traditional scope of industry research. For starters, genes themselves aren’t very informative. “Identifying an interesting gene is really just the first step in innovation,” Wenjun observed. “A lot of the time, the genetics points to a gene about which very little is known. What is the gene’s function? Which cells express the gene? What type of protein does it make? What happens when you over-express the protein or knock it out?”

The willingness to tackle such questions “is a big difference between how industry operates now and how we operated for decades,” said Deshaies. “In the past, we found targets by delving into the scientific literature and looking for proteins that already had extensive evidence linking them to disease. In most cases, academic labs had been working on these targets for years or decades, allowing industry researchers to form hypotheses about how they contribute to disease progression.

“Because little is known about most of the targets implicated by human genetics, the onus then falls upon us to develop basic knowledge about the biology. It’s very challenging work, but it also puts us in a position to build a trove of information on promising targets. And often, these are targets that other people probably don’t even know about yet.”

“We are definitely very excited about this approach,” said Wenjun. “By working closely with deCODE, we’ve found some novel genes and pathways. Hopefully, we can turn at least some of these ideas into really innovative medicines.”

“In the long run, it probably won’t be sufficient to inactivate just one brake on the immune cells. We may need to inactivate multiple brakes at the same time, so that cancer cells can’t mutate fast enough to come up with ways to shut down immune cells.”
Ray Deshaies
The right tools and the right talent

New technologies make it possible for biopharma scientists to generate useful results from basic research far more quickly than in the past. “In the last five years, we’ve witnessed a revolution in the tools we have available to study novel biology,” said Martin. “They include CRISPR, a very efficient way to do gene editing, and viral vectors, which we can put into cells to regulate genes up or down at will.  We can grow organoids, or mini-organs, out of normal and cancer cells from humans. Single-cell RNA sequencing enables us to identify every gene that’s active in an immune cell or cancer cell.”

Making the most of these tools requires highly talented scientists who can spot the clues hidden in massive amounts of data and assemble them into insights. Wenjun’s reputation for cutting-edge research was recently strengthened by two landmark studies done in collaboration with scientists from Peking University.

The studies provided the most in-depth look to date at the behavior of T cells in cancer, and why they can fail to attack cancer on their own or in response to immune-boosting agents. The China-based team, led by Zemin Zhang, did single-cell RNA sequencing on thousands of T cells taken from patients, including six with liver cancer in one study and 12 with colorectal cancer in the other. Wenjun and his team analyzed the resulting mountains of data to pinpoint specific factors that could account for the inertia of T cells adjacent to tumor cells.

The research uncovered new genes of interest as well as new subtypes of T cells that help explain immune passivity in cancer and offer clues on how to reverse it. “If our hypotheses are true, that will potentially give us new ways to target or convert T cells inside the tumor,” Wenjun said.

 

Flavius Martin, VP, Oncology Research

A lesson from HIV

New types of checkpoint inhibitors are one part of a larger strategy to overwhelm the ability of tumors to survive through constant mutations. “A big challenge in treating cancer is that cancer cells keep changing,” said Wenjun. “That’s the reason so many therapies work for a while but then stop working.”

Several strategies are being tried to overcome this problem. One is to develop new treatment modalities like BiTE® antibody constructs, a technology platform pioneered by Amgen. These bispecific T cell engagers link T cells to specific tumor targets, enabling T cells to recognize and kill cancer cells. By changing the tumor-targeting arm of these molecules, BiTE® antibody constructs potentially can be deployed against many types of liquid and solid tumors. Amgen has about a dozen BiTE® products in development, and one approved therapy.

In addition, a massive effort is underway across the industry to test immune-boosting agents either in tandem or in combination with other cancer drugs. Combinations could overcome a key limitation of first-generation checkpoint inhibitors. “Most advanced solid cancers are known as cold tumors,” said Martin. “Unlike hot tumors, they are not infiltrated by immune cells, so they don’t respond well to current checkpoint inhibitors.” Combination therapies might help to recruit immune cells to cold tumors, making checkpoint inhibition more effective.

“In the long run, it probably won’t be sufficient to inactivate just one brake on the immune cells,” said Deshaies. “We may need to inactivate multiple brakes at the same time, so that cancer cells can’t mutate fast enough to come up with ways to shut down immune cells.”

Deshaies noted that a similar treatment strategy has been effective against hard-to-treat viruses, which also use mutations to develop drug resistance. “In the end, what succeeded in HIV infection was having three separate ways to attack the virus combined in a single pill. It’s very likely that this approach will be necessary in cancer treatment as well. We’re still on the first generation of checkpoint therapies, but I expect there will be a second and third generation. By combining these molecules with other immunotherapies and targeted agents, I believe we’ll eventually have a cure for most cancers.”

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