by Ryan Ripsman
It is well known that cancer can appear suddenly, seemingly without cause, and kill an otherwise healthy person in a matter of months. It is less well known that this story sometimes happens in reverse. Rarely, a tumor that has spread across a patient’s body can spontaneously disappear. It was cases of spontaneous remission that set the ball rolling on one of the most promising families of cancer treatments – immunotherapies.
In the mid 19th century two German doctors saw cases of spontaneous remission of cancer after their patients were infected with erysipelas, an illness caused by bacteria. Concluding that the infection was the cause of the remission, the two doctors began to purposefully infect patients with the pathogen, hoping to induce remission. Surprisingly, it worked. Patients facing incredible odds, would see their cancers disappear after infection with erysipelas.
While the treatment was undeniably effective, it was quickly buried in the annals of medicine, and never achieved widespread use. The reluctance to pursue such a promising treatment can be attributed to two issues. First, the treatment was dangerous, in some cases, the erysipelas would kill the patient faster than their tumor would have. In other cases, the erysipelas would be ineffective resulting in a patient with both a bacterial infection and a tumor. But that alone would not be enough to condemn the treatment. Many cancer treatments can be dangerous, and few are uniformly successful at resolving the cancer. The metaphorical nail in the coffin of this treatment was that no one could explain why it should work. Why would infecting these already sick patients with another disease help treat their cancer?
Science would not have the right tools to understand these questions until the mid-20th century, 80 years after the treatment was first used. Scientists began to understand that the immune system plays an important role in the development of cancer. Cancer cells are defined by mutations, which are spontaneous changes in a cell’s DNA. DNA is part of a complicated system that acts as an instruction for the cell, telling it what proteins to produce. When mutations occur, they can change the proteins that a cell makes. Some mutations prevent cells from producing certain proteins, while other mutations allow cells to produce new proteins, called neoantigens. Cells have a built-in mechanism for manifesting their health, called the major histocompatibility complex class 1 (MHC-1 complex). Certain proteins can bind to the MHC-1 complex, which displays them to the immune system. When neoantigens bind to the MHC-1 complex, they alert the immune system that the cell is not healthy. The immune system can then kill the cell to prevent the development of a tumor.
When a tumor does develop, it is because it has found some way to evade the immune system. Tumors have many different methods for protecting themselves from the immune system. Some tumors with few neoantigens can remain invisible to the immune system. Other tumors can develop methods for inactivating the immune system. The patients treated by the erysipelas likely had inactive immune systems. The bacterial infection activated the immune system, allowing it to recognize and kill not only the bacteria, but also the cancer that had been plaguing the patients. This idea forms the underpinning of cancer immunotherapy. Immunotherapies all act to either help the immune system recognize a cancer cell that was previously invisible or activate a dormant immune system.
One common way a tumor can deactivate the immune system is by utilizing immune checkpoints. Immune checkpoints are proteins found on immune cells which can interact with proteins found on regular human cells. These checkpoints act as an off switch for the immune system, preventing the immune system from attacking their host. Some cancer cells can hijack these switches and use them to protect themselves from the immune system. In the early 1990s, two groups of scientists independently developed antibodies that can bind to these switches, preventing cancer from turning off the immune system. These drugs, called immune checkpoint inhibitors, were extremely successful, leading to a Nobel prize for their discoverers.
To see the amazing power of immune checkpoint inhibitors, consider the case of metastatic melanoma. Melanoma, when caught early, can easily be treated by a combination of surgery and radiation therapy, with an almost 100% success rate for up to stage II tumors. However, when melanoma spreads from its original location, a process called metastasis, it becomes deadly. Before the approval of the first immune checkpoint inhibitors, a mere 10% of patients with metastatic melanoma survived for 5 years. In a new study this number grew to over 50% when the metastatic melanoma was treated with two types of immune checkpoint inhibitors.
Immune checkpoint inhibitors do not work for all patients. Patients whose tumors have few neoantigens do not tend to respond well to immune checkpoint inhibitors, because their tumors are not sufficiently visible to the immune system. Additionally, some tumors which initially respond to immune checkpoint inhibitors can over time develop resistance to the therapy. Finally, in some cases, immune checkpoint inhibitors can cause immune cells to go rogue. This immune response is so severe that it can kill the patient.
Immune checkpoint inhibitors are not the only promising immunotherapy. Certain patients with tumors which are not recognizable by the immune system can benefit from CAR T-cell therapy. In CAR T-cell therapy, T-cells, which are a type of immune cell, are harvested from the patient. These T-cells are then modified so they can recognize one of the neoantigens produced by the cancer cells. The modified T-cells are injected back into the patient’s bloodstream so they can attack the tumor. Like immune checkpoint inhibitors, CAR T-cell therapy can sometimes cause the immune system to attack normal cells. CAR T-cell therapy is also extremely expensive as it must be prepared specially for each patient, using their own T-cells. Because of its high cost, some patients who would benefit from this therapy are not able to receive it.
More general immunotherapies also exist, like interferons. Interferons are particles released by the immune system. They signal the existence of a pathogen and induce a stronger immune response. Interferons can be given to patients to induce a stronger immune response against cancer.
The future of immunotherapy is bright. Many different companies and research groups are dedicated to developing new immunotherapies and improving existing ones. One large area of research is trying to predict who will respond well to various immunotherapies. Researchers and doctors can do this using next generation sequencing techniques. Next generation sequencing, among other things, allows scientists to look at all of a cell’s DNA. Information found in the DNA from a patient’s healthy cells and the DNA from their cancerous cells can be used to predict whether a patient is likely to respond well to different immunotherapies. For example, it has been shown that patients who have more mutations are more likely to respond to immune checkpoint inhibitors. It is very important that more of these biomarkers are discovered, so every patient can receive their ideal therapy.
With the advent of immunotherapy, we now have a new, powerful set of tools for combating cancer. While cancer is a formidable disease that will likely plague humankind for years to come, immunotherapies will change the way we view cancer. The study of immunotherapy is still in its infancy: the first immune checkpoint inhibitor was approved by the FDA in 2011 and the first CAR T-cell therapy was approved in 2017. Over the last ten years, immunotherapies have modified some deadly cancers into survivable illnesses. Who knows what improvements and innovations the next ten years have in store?