A Popular Science View of Checkpoint Inhibitor Cancer Immunotherapies
Checkpoint inhibitor therapies are a demonstrably successful approach to cancer immunotherapy. They suppress a mechanism that normally restrains immune cells from attacking other cells. This mechanism is abused by cancers, alongside a variety of other ways in which the immune system can be subverted or quieted. Any advanced tumor tends to have evolved into a state in which it is ignored or even helped by the immune system. Checkpoint inhibitor therapies are an improvement on chemotherapy when it comes to the trade-off between harming the cancer and harming the patient, as well as in the odds of success, but still present risks to patients. Immune checkpoints exist to prevent autoimmunity, and rampant autoimmunity can be just as deadly as any cancer.
Our usual defence against disease is our immune system. It does an excellent job of sorting out what doesn't belong in the body and attacking it - except when it comes to cancer. The checkpoint inhibitor breakthrough was the realisation that the immune system wasn't ignoring cancer. Instead, cancer was taking advantage of tricks that shut down the immune system. When stimulated, the T cell protein CTLA-4 acted like a circuit breaker on immune response. These brakes, which he called checkpoints, kept the cell killers from going out of control and trashing healthy body cells. Cancer took advantage of those brakes to survive and thrive.
In 1994, researchers developed an antibody that blocked CTLA-4. When they injected it into cancerous mice, the antibody jammed behind CTLA-4's brake pedal and prevented the T-cell attack from being stopped. Instead, the T-cells destroyed the tumours and cured the cancer. In 2011, that anti-CTLA-4 drug would gain approval as ipilimumab for use treating melanoma; it has since been approved to treat kidney and colorectal cancer. As a drug, it has saved many thousands of lives. Blocking the brakes on the immune system turned out to cause serious toxicities in some patients, but as a proof of concept, the success of ipilimumab proved that the immune system could, in fact, be weaponised against cancer. It also kicked off the search for newer, better immune checkpoints.
The first to be discovered was called PD-1. PD-1 is part of a sort of secret handshake that body cells give a T cell, telling it: "I'm one of you, don't attack." Cancers co-opted this secret handshake, tricking T cells into believing they were normal, healthy body cells. But that handshake could be blocked, creating a more precise cancer-killing machine with far fewer toxic side-effects than blocking CTLA-4. For many people, the anti-PD-1 drug pembrolizumab, approved in 2015 and sold as Keytruda, was the first and only thing they'd heard about cancer immunotherapy. Keytruda is currently one of the most widely used of the new class of drugs, approved for use against nine different types of cancer in the US, and a smaller number in the UK, and that list is growing rapidly.
Seven years after the approval of that first checkpoint inhibitor, there are reportedly 940 "new" cancer immunotherapeutic drugs being tested in the clinic by more than half-a-million cancer patients in more than 3,000 clinical trials, with over 1,000 more in the preclinical phase. Those numbers are dwarfed by the number of trials testing immunotherapy combinations or using them in concert with chemotherapy or radiation, which essentially turn the dead tumour into a cancer vaccine. It's hoped that, with checkpoint inhibitors releasing the brakes, the immune system can effectively finish up what the chemotherapy starts.