The 2018 Nobel Prize in Physiology or Medicine was awarded yesterday to James Allison and Tasuku Honjo for their “discovery of cancer therapy by inhibition of negative immune regulation”. Their efforts have laid the groundwork for a whole new field of cancer therapy: immune checkpoint therapy.   

The idea of using a small spaceship, preferably transporting tiny robots, to enter the body and kill off tumors or cancer cells is alluring. But nano-robotic therapies are unfortunately not available yet. Instead, what if we could harness the power of tiny warriors that are already in our bodies?

Illustration of a cancer cell and lymphocytes. Credit: man_at_mouse.

In the last 100 years, scientists have been trying to manipulate immune cells (think white blood cells) to kill cancer cells. Unfortunately, these therapies have been largely without success until most recently.

Immune cells are highly efficient at recognizing self from non-self. This means that they can selectively attack strangers in our bodies, such as bacteria or viruses, while not attacking our body’s own cells. But in the case of cancer, immune cells need to recognize, kill and remove “self”, because our cancer cell ARE us, just with slight modifications. The immune response to “self” or cancer must be finely tuned because immune cells that are too eager can do serious damage and set off autoimmune disorders. T-cells are immune cells that specialize in cell-cell-interactions. They can activate other immune cells, kill cells that are infected with intracellular pathogens and recognize and kill cancer cells. They use specialized receptors on their surfaces, called T-cell receptors, to test (like a pass-fail exam) molecules presented on the surface of other cells. T-cells can recognize cancer cells because they often have altered or mutated molecules on their surface. Once recognized by the immune system, these cancer cells are eliminated by Natural Killer cells [Editor’s note: Arguably the cells in our body with the coolest name!] or a subset of T-cells called cytotoxic T-cells.

A T-cell encounters an antigen on the surface of an infected cell. T-cells direct and regulate immune responses and attack infected or cancerous cells.
A T-cell encounters an antigen on the surface of an infected cell. T-cells direct and regulate immune responses and attack infected or cancerous cells.

But cancer is sly. To protect themselves from immune cells, cancer cells can remove their surface receptors or other molecules that are recognized by the immune system. This “molecular disguise” leaves T-cells and other immune cells unaware of what is going on. In addition, the local microenvironment surrounding a tumor can be highly immunosuppressive. It is a puzzling fact that a tumor can be surrounded by T-cells that do nothing to kill it.

One way for cancer cells to suppress T-cells is by the use of checkpoint proteins. These proteins normally protect against autoimmunity (when your body turns on itself) by acting as “brakes” that prevent T-cells from activating. Checkpoint proteins can be found on antigen-presenting cells, but they are also leveraged by cancer cells, giving them the ability to directly turn off our T-cells.

This year’s recipients of the Nobel Prize in Physiology or Medicine, James Allison and Tasuku Honjo, found that lifting these “brakes” could unleash the power of T-cells to kill cancer cells. In 1996, James Allison published the first study showing that an inhibitor that blocked the checkpoint protein CTLA-4 allowed T-cells to activate and kill cancer cells, resulting in reduced tumors in mice. For example, dendritic cells present cancer cell antigens (molecules that the immune system can recognize as foreign or harmful) to T-cells, priming them to recognize and attack the cancer cells. This priming, however, is negatively regulated by CTLA-4. The checkpoint protein CTLA-4 is a receptor on the T-cell membrane that blocks activation of the T-cell by dendritic cells. Inhibit this protein, however, and T-cells can get back to killing cancer cells.

PD-1, Tasukui Honjo’s research focus, works a little differently. Cancer cells use PD-1 to deactivate T-cells. Blocking this protein reduces the immunosuppressive effects of tumors. Since tumors are often surrounded by “sleeping” or deactivated T-cells, preventing their suppression can result in effective killing of the tumor.

Drugs targeting CTLA-4 or PD-1 (and other checkpoint proteins), alone or in combination, are now in use against several difficult-to-treat cancers, and more clinical studies are on the way. The results are no short of amazing, with regression of cancers against which other therapies have failed.

The dangers of setting the immune system loose are clear from these studies, however. The side effects of overactive immune cells roaming the body can be serious; in a few cases, a patient has died from treatment with immunotherapies. In addition, lifting the “brakes” on immune cells with particular checkpoint inhibitors does not work for all patients, underscoring how complex and personal cancer is.

Even so, in the words of the Nobel committee, “immunotherapy has revolutionized cancer treatment and has fundamentally changed how we view how cancer can be managed”. The future holds great promise as scientists work to discover how drugs can be combined and matched specifically to cancer cells expressing a given set of proteins. It might have taken a 100 years, but finally we are beginning to control the immune system and set it up to win the battle against cancer.

Learn more: Nobel Prize in Physiology or Medicine, 2018

Read more at the NYTimes: Doctors are using immunotherapy to help the cells of the immune system recognize and attack cancer cells