Behind the Cycle

Maybe it’s in a lab filled with bubbling test tubes and whirring centrifuges, maybe it’s in a paper-strewn office, maybe both, but the scientist is scribbling. He (or she) is wild eyed and often wild haired. He draws letters and arrows and formulas. He fills white boards and chalk boards and windows. Windows are good, because you can see both the writing and the crazed writer.

The Cancer-Immunity Cycle developed by Dan Chen and Ira Mellman has become the intellectual framework for cancer immunotherapy research. See below for a slideshow that explains each step of the cycle.

You know this "Eureka!" moment, you’ve seen it before. It’s what scientific breakthrough looks like in the movies. And, pretty much, what science never looks like in real life.

In real life, it looks like this:

First, the bar. It’s a decent sort of everyman tavern in the San Francisco sense, meaning a Dogpatch wine bar with organic varietals and easy parking and a Tuesday trivia night, a place located about fifteen minutes drive north from the Oyster Point industrial park where Genentech’s steel and glass laboratories front the San Francisco Bay. At a corner table, two of the customers sit close, talking excitedly, doodling on their napkins. They seem ecstatic. And maybe a little tipsy.

About them: Here, they are Ira and Dan, semi-regulars from the after-work crowd. To the casual observer looking up from his laptop, the two are a sort of odd couple. The guy on the left is a Greenwich Village-born professor-type, a crunchy academic who’d look right at home in a patch-elbowed jacket or tuning a mandolin. The guy on the right is perhaps 15 years younger and Northern Californian by way of Boston, with neatly textured hair and nattily outfitted in fitted button-down shirts. The first impression is of a friendly startup CEO who also plays in a competitive basketball league at the Y.

Dan Chen (left) and Ira Mellman.

In fact, the two have a great deal in common beyond a love of good music and good wine. For starters, both are scientists, and heavy hitters. Ira Mellman, PhD, is a scientist with an index line in probably every cell biology textbook around. A member of the National Academy of Sciences and former Yale Professor who’s received more academic distinctions than most people have hot dinners. Dan Chen, MD, PhD, is an oncologist and former Howard Hughes Medical Institute Associate who ran the Stanford University Cancer Center’s metastatic melanoma clinic.

Both ditched rock star academic careers for Genentech. Both are leading authorities on the human immune system. And both are at war against a common enemy: cancer.

Already, they’ve gone far, creating an entire pipeline of promising immunotherapy investigational medicines at Genentech. To go further, they need to create something new — a breakthrough moment, just like in the movies. Preferably one with a happy ending.

Cancer uses a sort of “cellular camouflage”, tricking the immune system into seeing it as a normal cell. Cancer Immunotherapy seeks to strip away that camouflage.

The human immune system is a personalized killing machine, specialized in recognizing and attacking anything “foreign” in the body, such as viruses, bacteria, and even the body’s own mutated cells. It’s a remarkably elegant and complex system coded by trial and error over the span of genetic history, and it does a remarkable job, 99.9999% of the time. The problem comes with that 0.0001%.

Cancer is essentially that 0.0001%; a cell which has dangerously mutated, but which the immune system fails to recognize or kill. In effect, cancer uses a sort of “cellular camouflage”, tricking the immune system into seeing it as a normal cell. Cancer Immunotherapy seeks to strip away that camouflage, so that the immune system can effectively recognize, target and destroy the mutated cells, before they destroy us.

Putting Research to Work

When it’s not in this bar, the front line of that war is in that lab down the road, where Dr. Mellman is the Genentech Vice President of Cancer Immunology, and Dr. Chen is Cancer Immunotherapy Franchise Head. Essentially, Mellman is responsible for building the teams responsible for developing the next generation of therapies that use the human immune system to recognize and destroy cancer. Chen is where the rubber meets the road.

Ira Mellman didn’t start out intending to become a cancer immunologist, or even a scientist. He moved from his native New York to Oberlin College in Ohio, intending to follow his father’s advice to translate his facility with instruments into a career in music, until an undergrad biology course changed his mind. A doctorate at Yale and postdoctoral work at Rockefeller University followed before he returned to Yale to begin a distinguished 20-plus year career most scientists only dream about. Mellman enjoyed the work, and he was good at it. He was med school faculty, a department chair, Cancer Center Director — a man on top of his field. But he wanted to do more.

For Mellman, the decision to leave a coveted academic post had less to do with career than with people — two of his children coping with chronic inflammatory disease, and each year saw more friends succumbing to the ravages of cancer. “To see that, and then being presented with the opportunity of moving to what’s the best place on earth to do drug discovery — I don’t know if it’s a moral obligation to act on that,” Mellman explained. “But it certainly was a motivating force for me.”

If Ira Mellman’s route from ivory tower to the forward edge of biotech drug development was a meandering path, Dan Chen’s road was expressway direct. Even as a child, Chen never doubted that he’d be anything but a scientist, like his parents, émigrés who left China and Taiwan for the green hills and high energy physics laboratories of UC Berkeley. He went from MIT to USC to Stanford, picking up degrees in Molecular Biology, Immunology and Medicine. After a medical oncology fellowship, he also completed a post doc work in the laboratory of one of the most well-known immunologists in the field, Mark Davis, who had discovered the T-cell receptor.

The combination of an MD and PhD allowed Chen the opportunity to care for cancer patients, and then study their disease in the laboratory.

“It’s difficult to imagine anything more motivating,” Chen explained. “As a doctor, you go through this life and death battle with your patients. Back in the lab, you know you have to solve the cancer problem, to save these people. And there is the boundless hope that by understanding the underlying biology, that you’ll be able to come back with something better for them. That interplay really drives what you do as a scientist. You can see just how badly you need to make a breakthrough.”

To be presented with the opportunity of moving to the best place on earth to do drug discovery — I don’t know if it’s a moral obligation to act on that, but it certainly was a motivating force for me
– Ira Mellman

Unfortunately, in the early days of cancer immunotherapy, breakthroughs were hard to come by.

A Promise Deferred

While cancer immunotherapy is the newest weapon in the war against the disease, the concept has been around since the early 1900’s. Applying the power of the immune system to cancer promised powerful, long term, durable therapies, and a future where tumors are vaccinated against and fought by the body like a cut or a cold. But for most of the field’s history, cancer immunotherapy has failed to deliver on that promise.

“At first, it was sort of pushed off in the corner.” Mellman explains, “In part because so little was known about the immune system at that time, and in part because the work just wasn’t very good, from a scientific perspective.”

“We had the small steps,” Chen says. “We believed the biology was there. But was it always going to be 20 years away before we had something that was really useful for patients? None of us could really say when the actual breakthrough was going to happen.”

For decades, immunologists had demonstrated the capacity of the immune system to recognize and kill cancer cells in the laboratory. The problem was, they couldn’t reliably translate those same results in patients.

That picture started to change as researchers made advances in understanding the underlying biology of the immune system, and honed in on a number of factors in the tumor microenvironment. Of particular promise was a protein called PD-L1, which jammed the immune system’s ability to recognize cancer cells.

“In the early days, you really had to squint at the data to see anything positive,” Chen says. “You started to ask yourself, am I wrong in having faith in this therapy? But PD-L1 really changed that.”

We now have a good idea which patients will be responsive to cancer immunotherapy. And for them, the results can be transformative.
– Dan Chen

A New Value Proposition

Mellman had written about PD-L1 as a potential target in 2005, while still at Yale. And Chen, even before joining Genentech in 2006, had a conviction that PD-L1 was a prime candidate for the “missing link” to unlocking the immune response. Soon, Chen had the chance to test those suspicions in clinical trials, and in his own oncology practice.

“Immunotherapy is totally different than any other type of therapy,” explains Chen, who still maintains a clinical presence as a Stanford oncologist and a close, emotional connection with his patients. “It’s a different value proposition. At this stage, it still doesn’t work for every patient. Maybe I only get a 10 or 20 percent response rate. But we now have a good idea which patients will be responsive. And for them, the results can be transformative.”

“When you have a stage 4 patient with terminal cancer get their life back, their family back — not just for months, but for three, five, ten years — that’s meaningful,” Chen says. “And if you ask a patient with terminal cancer what they really want, that’s what they want. They’ll take two months. But more than anything, they want their lives back."

Countdown to the Future

It was just this argument that convinced Genentech to radically expand its research direction.

For Chen, it felt like the puzzle pieces of his life, all the training and research, the experience with oncology and biomarkers and his early interest in PD-L1, were all coming together. For Mellman, whose storied academic history had been interwoven with the history of immunology for decades, it was the realization of the goals set when he left academia, a chance to translate his academic chops into real-world solutions. They had a green light. The clock was ticking.

As Chen remembers it, it took about two years to reach their goal. They had new therapies lined up in the development pipeline, had retooled Genentech into a leader in cancer immunology research and therapeutics, and were uncovering new facts about how the immune system works on a nearly daily basis. Along the way, researchers across the globe had uncovered vast new swaths of science — new proteins, new biomarkers, new information about cancer and immunology, cell biology and clinical oncology. That work had produced a load of important studies and papers.

Reviews of the previous literature are common in academia, a sort of helpful extra credit. But Mellman was in a unique position to realize that his field was at a tipping point. Rather than merely summarizing the recent articles, he wondered, was it possible to attempt to summarize the entire cancer immunology process?

Cancer Immunology is still the new kid on the block, a sort of hybrid field at the intersection of disparate areas of expertise. It’s a complicated science with a lot of moving parts, co-factors and interactions and plagued by problems of organization and complexity. Each field was complicated, the immune system, especially. Meanwhile cancer has its own set of rules — and in effect, a whole other field of biology.

As a scientist in charge of a research team, Mellman’s job would be a great deal simpler with a rational map of this biological terrain. Not just snapshots from different areas, but a big picture of the whole thing from the air. He needed someone creative, smart, specialized but not narrow. Mellman picked up the phone, and dialed Dan Chen, who had been thinking about this very problem.

Mellman was in a unique position to realize that his field was at a tipping point.

In Vino Veritas

They started in Mellman’s office, just bouncing ideas. But was the “big picture” a list or a chart or a drawing? The right answer might help the field conceptualize the entire problem.

It was fun — big concepts flowing fast and loose, like-minded experts listening and riffing off each other, the ideas evolving with iteration. They spent the morning like that, then the afternoon. The talking turned to scribbling. They filled pads, then whiteboards. Nobody tried writing on the windows, not yet, but it didn’t matter. They were en route to their breakthrough, but they weren’t there yet.

They already had a grip on the biology. They were experts in that. That’s what filled the whiteboards with scribbles and colors and words. It was complete, but complicated. Could they simplify? To render the whole complicated dance in a single elegant figure? A grip wasn’t the problem. What they needed was to let themselves go.

“Like most good things, this one started in a bar,” Mellman laughs. At Genentech, it’s known as Ira’s “San Francisco office”. Any time a meeting dragged on after five or six, that was the place.

“It’s a little bit of a hipster haven type place, but everyone’s comfortable,” Ira explains. He’d gone there with lots of people. The afterhours pow wows with friends and co-workers were fun, sometimes even productive. Today, he went with Dan.

It was fun — big concepts flowing fast and loose, like-minded experts listening and riffing off each other, the ideas evolving with iteration.

“We had a fair amount to drink, and all of the loose concepts that we had, they came together,” Chen laughs. “And so we really gelled. And that was a perfect moment of the two of us bringing together ideas, concepts, an over-arching figure. And that’s where it started.”

The pens came out. The minutes turned into hours, the ideas turned into sketches. A few years earlier, Mellman had written a review in Nature. It included a diagram with a few steps describing how the immune system can kill cancer. “We were looking at that, and Dan said, ‘I think this process is a circle, a cycle’” Mellman remembers. “‘and we can blow this up to give it a bit more resolution, so we can see each of the things that has to occur. How do we do that?’” They ordered another round. Then they worked on it some more.

The next day, they presented Genentech’s in-house graphic artist, Allison Bruce, with a pile of wine-stained cocktail napkins. There, amongst the sustainable Napa tannins, was a circle of arrows. Between the arrows were seven circles, each with a drawing.

This was, in simple cartoon form, the positive feedback loop of how the immune system recognizes and kills a cancer cell. Mellman referred to it as a “cancer-immunity cycle.” “When those words came out of his mouth, I knew we had the name we needed,” said Chen. That pretty much said it.

A Promise Delivered

“I don’t think there was anything creative about that,” Mellman explains. “But it was a different way of conceptualizing the work everyone in the field had done. We just were able to string together a lot of really disparate thoughts and realized, gee, all these things fit in a circle! And they feed back on each other!”

There, amongst the sustainable Napa tannins, was a circle of arrows. Between the arrows were seven circles, each with a drawing.

For Chen and Mellman, the conceptual breakthrough was in framing the biology as a tool they could use practically.

“In any one patient, the cycle can fail at any one of a number of points. And if we can figure out which is the failure point for any one patient, then we can figure out what it is we have to do for that patient,” Mellman explained. “And that was it.”

It was simple, and manageable. And in retrospect, Mellman says, almost obvious. “But in some ways, the best concepts are the ones that, when you come up with it, you sort of kick yourself and say, ‘why couldn’t I think of that five years ago?’ It just wasn’t done.”

Philosophically, we believe we have a responsibility — as scientists, as a company — to help the larger field.
– Dan Chen

The impact of their work was immediate, and widespread. Their map resulted in a seminal article that continues to provide an intellectual framework for cancer immunotherapy research around the world.

Chen acknowledges that the world of biotech is competitive, and the thought did cross their mind not to share this new tool. “That lasted about 30 seconds,” Chen laughs. “Philosophically, we believe we have a responsibility — as scientists, as a company — to help the larger field.”

The advances are galloping now, altering the research landscape, and changing the promise of cancer immunotherapy. Today, Mellman and Chen are working on more than 20 different investigational medicines targeting four different steps of the cycle. It’s no longer a naïve dream, twenty years away — it’s now. And the now is changing fast.

“That’s the way it is with breakthroughs,” Chen explains. “They’re very sudden. Everything looks different. You no longer need to squint at the data, and wonder if it’s working. It’s obvious. And it changes everything.”