Today, the Nobel Prize Committee has honored two researchers for their role in pioneering a new avenue for cancer treatment, one where the therapy targets the immune system, which then goes on to attack the cancer. The researchers, James Allison of the MD Anderson Cancer Center and Tasuku Honjo of Kyoto University, worked separately to identify and target proteins that help keep the immune system from attacking other cells in the body.
Immunity and cancer
Our thinking about the relationship between the immune system and cancer has undergone a number of revisions over the last century. The initial question—why doesn’t the immune system attack cancers?—was seemingly answered as people developed a better understanding of how it normally keeps from attacking healthy cells. Under this view, cancer cells looked too much like a normal cell to generate a response.
But this turned out to be not quite right. People taking immunosuppressive drugs over long periods tended to have increased incidence of cancer, suggesting that the immune system was attacking and eliminating cancers all the time. The question then became one of why the immune system wasn’t effective against some cancers.
That question has now led to two promising approaches to treating cancer. The one honored today is called CAR T-cell therapy, and it’s focused on one possible answer to this question: the tumor cells are hard to recognize. In CAR T-cell therapy, researchers handle the recognition for the immune system by engineering a protein that sticks to a specific type of tumor cell, and that protein plugs in to the normal immune response of T cells. By isolating a patient’s own T cells and engineering them to make this protein, the immune response can be directed specifically against the tumor.
The Nobel Prize this year is going to what’s called immune checkpoint therapy. It comes from an alternate answer to the question of why the immune system isn’t effective against some cancers: the immune system recognizes them, but it gets shut down before it can mount an aggressive response.
Shutdown to rev up
T cells identify cells infected by pathogens because the pathogens induce the production of proteins that the immune system has never seen before. Cancer cells arise because of mutations that result in the production of altered proteins that can also be recognized as new to the immune system. But the recognition process involves multiple steps. One involves a specific recognition of the previously unseen molecule, which is handled by a protein called the T cell receptor. But to mount an immune response, that recognition has to be accompanied by signaling through an additional pathway that gives the T cell permission to attack.
This permission is the “checkpoint” in immune checkpoint therapy.
In the early 1990s, it gradually became clear that this checkpoint was carefully controlled. In addition to the signaling system that indicated that it was permissible to go ahead and attack, there were also inhibitors that told the immune system to back off. When either of these inhibitors (CTLA-4 or PD-1) was knocked out in mice, it resulted in autoimmune problems. In other words, without the checkpoint, the immune system could attack indiscriminately. In fact, the activation of the CTLA-4 system has been targeted to treat autoimmune disorders.
James Allison, by contrast, recognized the potential in blocking CTLA-4 and thereby releasing a limit on the immune response. That, he reasoned, would liberate T cells to attack tumors. And, conveniently, some of the antibodies used to identify CTLA-4 and the cells that express it would prevent it from interacting with other proteins. Allison’s lab used these in mice with tumors, and their work showed that the antibody treatment led to the elimination of the tumors.
Critically, and unlike most other therapies, the response wasn’t specific to limited types of tumors. Since the immune system was targeting the cells, it would work against anything that T cells could recognize. Early tests showed that it could treat melanoma, breast cancers, and prostate cancers.
Allison eventually found a small biotech firm that was interested in the approach (the company was later acquired by Bristol-Myers Squibb), and human trials were in progress in the early 2000s. These showed a pattern that has continued as research into immune checkpoint inhibitors has progressed: extremely strong responses, including lasting remission, in a subset of patients, along with elevated risk of autoimmune responses. While the autoimmune response could require long-term treatments or result in death, in many cases, the therapy put otherwise untreatable cancers into remission, with no need for further CTLA-4-targeting treatments.
In fact, the CTLA-4-targeting treatments were so effective in some cases that scans of the tumors shortly after treatment showed apparent growth, caused by the massive number of immune cells that entered the tumor to attack it.
Alternate route
Unlike Allison who leveraged the work of others on CTLA-4, Honjo was the first to identify the PD-1 protein. Unfortunately, it took his research group until the late 1990s to understand what the protein did. It gradually became clear that PD-1 acted on a separate checkpoint system from CTLA-4 but performed a similar function. And, critically, it was noticed that parts of the PD-1 checkpoint were active on tumor cells, suggesting they used it to evade immune attack.
Shortly after Allison’s approach showed promise in clinical trials, Honjo was validating PD-1-targeting antibodies as an anti-cancer agent in mice. In many ways, PD-1 inhibitors followed a similar path to CTLA-4 inhibitors through their development. But a PD-1 blockade was slightly more effective at activating an anti-tumor immune response, and it caused somewhat fewer autoimmune problems.
In any case, both quickly made their way into the clinic. The CTLA-targeting therapy was approved by the FDA in 2011; PD-1-targeting treatments were approved in 2014. Since the two target different pathways, they have also been used in combination.
The results, in many ways, are spectacular. In a melanoma study population, most patients would have been dead in two years; after treatment, more than 70 percent were still alive at 18 months. And, as mentioned earlier, the two treatments can be effective against a huge range of cancers, since they target the immune system and rely on that to provide specificity against different tumor types.
That said, the autoimmune problems have not gone away. In some cases, they can be fatal and in others will require life-long treatments for the side effects.
But there are still several areas for possible improvement. Over time, we’re building up larger samples of people who respond to these treatments, and we’re already starting to understand how some tumors continue to evade the immune system even after this checkpoint is released. And the current drugs in use are relatively crude, blocking the pathways they target entirely. As we learn more about the basic details of how the immune response is regulated, it’s possible that we could develop more specific therapies that have fewer side effects.
In any case, Allison and Honjo have played critical roles in changing our understanding of the relationship between the immune system and cancer. And they share an important distinction in that the change they enabled has directly resulted in therapies.
