C&B Notes

Cancer Immunotherapy Breakthrough

James Allison, winner of the 2018 Nobel prize in medicine, is a pioneer in understanding how to harness the human immune system to battle cancer.  These research findings are unlocking a powerful and transformative addition to cancer therapies.  His experience at the MD Anderson Cancer Center is reminiscent of Lockheed Martin’s Skunk Works (Ben Rich’s book about it is a great read), which had the mandate, flexibility, intellectual curiosity, and enterprising culture needed to make great leaps in defense technology in the second half of the 20th century.

Until very recently we’ve had three main methods for treating cancer. We’ve had surgery for at least 3,000 years. We added radiation therapy in 1896. Then in 1946, chemical warfare research led to the use of a mustard gas derivative to kill cancer cells. Those poisons were the foundation for chemotherapy. These “cut, burn, and poison” techniques are currently estimated to be able to cure cancer in about half of the people who develop the disease. And that’s remarkable, a true medical accomplishment. But that leaves the other half of cancer patients. Last year, in the United States alone, that translated to nearly 600,000 people who died of the disease. The fight was never fair. We’ve been pitting simple drugs against creative, mutating versions of our own cells, trying to kill the bad ones while sparing the good ones, and making ourselves sick in the process. And we’ve been doing that for a very long time. But now we have added a new and very different approach—one that doesn’t act directly on cancer, but rather acts on the immune system. And that’s the breakthrough.

The immune system has evolved over 500 million years into a personalized and highly effective natural defense against disease. It is a complex biology with a seemingly simple mission: to find and destroy anything that’s not supposed to be in our bodies. Hundreds of millions of immune cells circulate throughout the body, searching out and destroying invaders that make us sick and body cells that have become infected, have mutated, or have become defective—cells like cancer. Which raises the question: Why doesn’t the immune system fight cancer already, the way it fights even the common cold? For more than 100 years, medical researchers puzzled over that question. Most concluded that the immune system and cancer simply had nothing to say to each other. The argument was that since cancer is a normal body cell gone rogue, it is too much a part of us to ever trigger an immune response. Cancer immunotherapy was condemned as a quaint if simplistic idea based on high hopes and bad science. But despite the mounting mockery of the larger scientific community and dwindling research funds, a handful of immunotherapy researchers continued to believe—and continued searching, decade after decade, for the missing piece of the cancer immunity puzzle, a factor that prevented the immune system from recognizing and attacking cancer cells.

* * * * *

Allison’s lab now had a fairly complete picture of the steps required for T-cell activation against disease. First, the T cell needed to recognize the sick cell by its unique protein fingerprint; in other words, it needed to be presented with the antigen that matched up with its T-cell receptor. Usually it was a dendritic cell or macrophage that did that presenting. Binding to that antigen was like turning the key in an automobile ignition. The other two signals (CD28 and CTLA-4) were like the gas pedal and brake on the car. CTLA-4 was the brake—and it was the more powerful of the two. You could press both (and in experiments, Krummel found that was a crude way of controlling the activation rate), but if you floored both, the brake overruled the gas pedal and the T cell wouldn’t go, regardless of everything else. Or, more accurately, enough stimulation of CTLA-4 and immune response stalled out, regardless of how much the T cell was being triggered by a sick cell antigen.

If all this sounds complicated, it’s because it is, on purpose. Allison’s lab had discovered an elaborate safety mechanism, an aspect of the larger framework of checks and balances that prevents the immune system from going into overdrive and attacking healthy body cells. Each safety is a sort of fuse that gets tripped if a trigger-happy T cell is programmed to target the wrong antigen, such as ones found on normal body cells. It was a way of repeatedly asking Are you sure about this? before T cells turned into killing machines. Proper triggering of immune response against pathogens is what keeps you healthy. However, pedal-to-the-metal immune response against healthy self cells is autoimmune disease. The double-check, double-signal mechanism of T-cell activation would turn out to be only one of many redundancies and fail-safe feedback loops built into immune response. Those “checkpoints” on T-cell activation hadn’t been guessed at before.

* * * * *

Back in Texas, the MD Anderson Cancer Center was opening a new outpost lab near the town of Smithville. “Yeah, it was pretty weird.” Allison says. “Some economic stimulus thing from the governor, on donated land and with state money. And it was in the middle of an 18-acre state park. They’d just set up some lab buildings and hired six faculty members to go out there.” The idea was to fund a team to study carcinogenesis—how cancer starts. But in reality, Allison soon discovered, they pretty much had free reign. “Yeah, that was the weird thing at the time, because after they started this thing, the MD Anderson president changed. The new guy came in and said, “What do you do? What the hell is that?” You know? So they kind of just forgot about us and pretty much left us alone.” This was Allison’s kind of place. His colleagues were bright, enthusiastic scientists his own age—the oldest were in their thirties—who worked late, helped each other with their experiments, kept beer in the lab for ones that ran overnight, and pooled intellectual resources without ego or credit getting in the way. “It was great,” Allison says. “The camaraderie—nobody expected any payback for anything. They did it because it’s what you did, you know? It was heaven.”

The setup was sweetened by a total lack of teaching or administrative responsibilities, a Norton Commando 850 motorcycle, and enough NIH and NCI grant money to pursue what Allison was really interested in—the T cell. “It was a fantastic time in science because immunology had just been this poorly understood field,” he says. “I mean, everybody knew we had an immune system, because there were vaccines. But nobody knew much about the details of anything.”

Referenced In This Post