Self & Other · Cancer and the Immune System
Allison and Honjo
Coley’s intuition that the immune system could be turned against cancer floated, for most of the twentieth century, somewhere between fringe and dismissed. The argument against him was strong and not unreasonable: nobody could explain his results, the response rates were unpredictable, and the field of oncology had moved decisively toward radiation and chemotherapy. Drugs that killed dividing cells could be measured. Bacterial infusions that sometimes worked, in ways that no one understood, could not.
Through the 1950s and 1960s, a handful of researchers continued to argue that there was something there. Lewis Thomas, a beloved physician-essayist, proposed in 1959 that the immune system regularly catches and eliminates incipient cancers. Frank Macfarlane Burnet — the same Burnet from Chapter 3, the one who had imagined clonal selection — picked up Thomas’s idea and called it cancer immunosurveillance. The proposal was largely speculative. The evidence, in the 1960s, was thin. The mainstream of cancer research treated the idea politely and moved on.
A few people kept working. Steven Rosenberg, at the National Cancer Institute, spent the 1970s and 1980s on what he called adoptive cell therapy — taking T cells from patients, expanding them in the lab, sometimes engineering them, and giving them back. The early results were occasional dramatic responses in a few cancers, surrounded by many failures, in a field that mostly didn’t believe him. Rosenberg has written, with admirable honesty, about how lonely those decades were.
The breakthrough that changed everything came from a different angle, in the 1990s, from two laboratories on opposite sides of the world that had no idea they were working on the same problem.
Allison and Honjo
James Allison was a Texas-born immunologist who had spent his career studying T cells. By the 1990s he was working in Berkeley, focused on a particular molecule on the surface of T cells called CTLA-4. CTLA-4 had been described by other labs as a kind of secondary signal in T cell activation — a molecule that turned up on T cells once they had been activated and seemed, in some way, to be involved in regulating the response.
Allison’s lab found that CTLA-4 was, in essence, a brake.
When a T cell encountered an MHC molecule with a fragment its receptor recognized, it began to activate — to start the slow, careful process of dividing and producing the cytokines that would mobilize the rest of the immune system. CTLA-4, appearing on the cell’s surface as part of this activation, then stepped in and slowed the process down. It was a built-in safeguard. The T cell would activate to a point and then, partly through CTLA-4 binding to its target, calm itself back down. The brake existed, evolutionarily, to prevent T cells from running away with their responses — to prevent, in other words, the kinds of failures we have spent the last few chapters describing.
Allison’s question was different. He asked: what if the brake is also why the immune system fails to destroy cancer? What if, in cancer, T cells start to mount a response against the tumor and then, before they can do real damage, the brake comes on and shuts them down? What if the way to make the immune system effective against cancer was not to make it stronger, but to release it?
In 1996 he published a paper showing that, in mice, blocking CTLA-4 with an antibody allowed T cells to mount full responses against tumors that they had previously been unable to eliminate. The mice’s own immune systems, freed from the brake, destroyed cancers they had been ignoring.
Allison’s idea took years to be taken seriously. Pharmaceutical companies, interested in cancer drugs that killed cancer cells, were initially skeptical that you could treat cancer by adjusting a regulatory molecule on T cells. Allison spent the late 1990s pitching the idea to companies that mostly turned him down. Eventually, a small biotech took it on. The first antibody against CTLA-4, eventually named ipilimumab, was tested in patients with metastatic melanoma — a cancer with, at the time, a uniformly grim prognosis — starting in the early 2000s. The first results were striking. About one in five patients had durable responses, sometimes complete remissions, in a disease where five-year survival had previously been close to zero. Ipilimumab was approved by the FDA in 2011.
Around the same time, on the other side of the Pacific, a Japanese immunologist named Tasuku Honjo had discovered a different brake on T cells, called PD-1. Honjo had identified PD-1 in 1992, while studying programmed cell death (which is what the PD stands for), and only later realized that it functioned as another inhibitory signal in the immune system. Through the late 1990s and 2000s, Honjo and his collaborators worked out that cancer cells often display the natural ligand for PD-1 — a molecule called PD-L1 — on their surfaces, where it binds PD-1 on T cells and tells them to stand down. The cancer cell, in effect, was wearing a sign that said: I am not a threat, please ignore me. The T cells, reading the sign, complied.
Antibodies that blocked PD-1 — or that blocked PD-L1 on the cancer side — prevented this signal. T cells that would have been turned off near the tumor remained active. The first PD-1 blockers, drugs like pembrolizumab and nivolumab, were approved in 2014. They worked across a broader range of cancers than ipilimumab, with somewhat less severe side effects, and the response rates in some diseases — melanoma, certain lung cancers, certain kidney cancers — were beyond what oncology had ever seen for stage IV disease.