We tend to think of innovation as a moment of epiphany followed by an onward march toward disruption. Sure, there are always some twists and turns along the way, but fearless entrepreneurs seem to have no problem adapting, iterating and pivoting their way to incredible success.
That makes for inspiring stories, but the truth is that innovation more often follows a long and twisted path. Chief among the difficulties is the wide chasm — often known as the Valley of Death — that separates the discovery of important new insights and the development of a viable product. Many promising ideas never make it through.
That’s one of the things that makes James Allison’s development of Cancer Immunotherapy so inspiring. Not only is it achieving miraculous results, curing people with terminal cancer who once would have had no hope, but has led others to pursue similar research. The story also shows how hard it is to bring a major discovery to market, even if it’s a miracle cure.
An Early Passion For Solving Problems
Growing up as a doctor’s son in Alice, Texas in the 1960’s many expected Jim Allison to become a physician. He was naturally curious, loved playing with his chemistry set and would often accompany his father on house visits. But gradually it it became increasingly clear to Allison that a doctor’s life wasn’t for him.
“I realized at some point that, as a doctor, my father could never make mistakes, because when someone was sick they depended on him to make the right decisions. I just liked figuring things out and realized that as a scientist I could make as many mistakes as I needed to get the right answer. I also really wanted to help people, just like my dad, and believed I could do that as a scientist.”
It was a lucky break in high school that really set him on his path. He was invited to attend a summer course for high performing students at the University of Texas at Austin. For the first time he got to do serious experiments in a real lab. He was immediately hooked. Allison went on to attend UT Austin, eventually earning his PhD in Biochemistry in 1973.
During his graduate work, he became mesmerized by immunology. “T- cells had just been discovered,” he told me. “I was just fascinated by the whole idea of it. These cells would just cruise around and kill stuff for you and not hurt you.” He would spend the next 40 years of his life figuring out how it all worked.
And Ignition Switch, A Gas Pedal And A Brake
Our immune system is an amazing thing. We have a wide array of protein molecules, called antibodies, that act as roving bouncers in a club, checking the ID’s of every cell in our body. Once they encounter one that doesn’t belong, they bind to it and call in reinforcements, called T-cells, that attack the invader, called an antigen, and kill it.
The system is amazingly robust. T-cells can multiply every six hours, so our bodies can go from having just a few dozen of them to hundreds of thousands in a matter of days. That’s great when unwanted visitors choose to invade our bodies, but if left unchecked, our immune system can attack our own cells as well the essential bacteria that make up our microbiome.
So the regulation of our immune system is extremely important and Allison was curious to know how it all worked. His first major success was the discovery of the structure of CD-28, a protein that with bonds with another receptor, called B-7 to stimulate immune response. Together, they function as an ignition switch and gas pedal for the immune system.
Shortly after Allison’s discovery, another protein was discovered, called CTLA-4, that was very similar to the CD-28 gas pedal and most assumed that it had a similar function. However, Allison’s noticed that CTLA-4 didn’t appear until after the immune response had already started. If anything, he thought, it’s not a gas pedal, but a brake.
So once again, he took his hunch to the lab and, after his research confirmed it, he published his results. It turned out to be an enormous insight.
A New Model For Cancer Treatment
A further breakthrough in 1994 came when Allison’s colleague, Sarah Townsend, showed that the B-7 ignition switch inhibits tumors. This lead Allison to believe that a glitch in our immune system inhibits our ability to fight cancer. He also thought that if he could help our body to calibrate T-cell regulation, he could treat cancer in a new and revolutionary way.
First, he guessed that you need some tumor cells to die for the immune system to target cancer cells. That would cause the ignition switch to fire and the gas pedal to accelerate the immune response. However, it seemed that the brakes were being applied too early, inhibiting our natural defenses ability to fight cancer effectively.
So just as he had done his entire life, Allison got started figuring out the problem. He reasoned that “stepping on the gas” by stimulating the immune system would lead to problems, because it would cause T-cells to attack everywhere. But if he could just take off the brakes to an immune response already in progress, he just might be able to create a positive effect.
The results he published in 1996 were astounding. Mice injected with an antibody that slowed the CTLA-4 brakes on the immune system showed a rapid reduction in tumors and most were still cancer free after 70 days. What’s more, the mice he treated showed immunity when injected with new cancer cells.
The outcome surprised even Allison himself. “I was expecting it to slow the tumors a little bit, but the tumors completely melted away,” he says. It was, obviously, a major breakthrough.
Entering The Valley of Death
Jim Allison had been happy as a lab scientist. He wasn’t seeking fame or fortune, he was just in love with, as he put it, “figuring things out.” A discovery of these proportions, however, thrust him into a new role. “I consider myself a basic scientist,” he told me, “but when I saw this I said ‘boy, this thing has got to get translated into an effective treatment.’”
Soon he found himself flying around the country presenting his revolutionary results. He met with scientists at a dozen companies and sometimes was asked back to show his discovery to higher-ups. Nevertheless, the answer always came back the same — no. “It was depressing,” he told me. “I knew this discovery could make a difference, but nobody wanted to invest in it.”
The executives had reasons for their reticence. Other immunological approaches for cancer had been tried — hundreds of trials — and they all failed. Further, what Allison was proposing ran counter to the more targeted approaches coming into vogue. “We weren’t really treating cancer, just fiddling with switches,” he says. “The attitude was, ‘you’re not targeting, you think you’re just going to take the brakes off and it’s going to work?’”
So after nearly three years of trying to sell his idea, not to mention the decades he had spent building his reputation as a top notch research scientist, Allison was coming up empty. Finally, in 1999, a friend introduced him to a small biotech company in Princeton, called Mederex, that agreed to invest in his approach. It was, to be sure, a wise investment.
A Revolutionary Cancer Drug
By 2004, Allison had moved to the Memorial Sloan Kettering Cancer Center in New York City, where just a few floors down clinical trials for his revolutionary new approach were getting started. At around the same time, Sharon Belvin, just 22 years-old at the time, found that she had a very aggressive form of skin cancer.
Despite being in otherwise good health — she was an avid runner — the prognosis was poor. The skin cancer had already spread to her lungs and her doctors only gave her a 50% chance of survival. As she ran through the usual treatment options of surgery, chemotherapy and radiation, nothing seemed to slow the cancer’s spread.
It was then that her doctor, Jedd Wolchok, suggested that she participate in the clinical trial testing Allison’s approach. A new drug, called Ipilimumab or “Ippy” for short, had been developed based on his research and was now in Phase 1 testing. Belvin would be its first patient. Out of options, she agreed without hesitation.
She began 90 minute treatments every three weeks. The side effects were so mild that she said to her husband, “Why could they have not started me on this, rather than making me suffer through chemo?” After four rounds of treatment, the tumor in her lung had shrunk 60%. Some months later, in a meeting at Wolchok’s office, she found out that she was in remission.
Today, more than a decade later, Sharon Bevins has two children and works as a personal trainer. She is just one of many success stories. In 2011, Ipilimumab was approved by the FDA and is now marketed under the brand name Yervoy by Bristol-Myers Squibb, which acquired Mederex for 2.4 billion in 2009, largely on the strength of Allison’s idea.
Unlike those frustrating years he spent in the Valley of Death, the field of Cancer Immunotherapy which Allison spawned has become well established, with teams of doctors around the country working to find other switches they can flip to unleash our bodies’ natural defenses on cancer cells.
The breakthrough has also paved the way for another approach, called virotherapy, which injects reprogrammed viruses into tumors to provoke an immune response. Another development is combined approaches. One recent trial showed that combining Allison’s Ipilimumab with a similar drug boosted response from under 30% to almost 60%.
Allison has since moved to MD Anderson Cancer Center where immunotherapy has become a key aspect of its moonshots program. “Immunology is the fourth pillar of cancer therapy,” he says. “The problem is that we’ve got understand how these work together in combination. That’s what we’re doing at MD Anderson. We now know that we actually can cure cancer.”
Yet the Valley of Death still remains. All too often, we look at an enormous success like James Allison’s immunotherapy and all we see are the awards and the accolades (his Breakthrough Prize is shown above). Yet we often forget that any fundamental discovery involves not only excitement and triumph, but often also heartbreaking desperation.
The truth is that innovation is never a single event. While it’s nice to think that we can just come up with a big idea and iterate, adapt and pivot our way to success, at the heart of any major transformation is people like James Allison and his colleagues, who spend years of Sisyphean labor, quietly figuring things out.