by Apurva Govande
figures by Rebecca Clements

The single greatest challenge of fighting cancer is that cancerous cells come from our body’s own cells. Because cancer cells are similar to healthy cells, successfully and specifically targeting cancerous cells with minimal damage to healthy cells and tissue is difficult. A major advance against cancer in the past decade, cancer immunotherapy is a therapeutic treatment that helps our own immune systems recognize and fight against cancerous cells.

The ongoing war on cancer

Today, we have several forms of cancer therapy that are often used in combination with one another, and each therapy has its advantages and limitations. The ideal cancer therapy would target cancer cells with little to no damage to healthy cells. While this goal has not always been realized, successive advancements have reduced side effects and pushed treatment limitations. Surgically cutting out tumors, often along with surrounding healthy cells and tissue, was the earliest form of cancer therapy. Surgery is useful for tumors isolated in one part of the body but cannot completely remove the cancer if cancerous cells have traveled to other parts of the body, a disease progression called metastasis. Soon following the surgical approach was  radiation, which damages and kills cancer cells but is also toxic to healthy cells. Radiation can target tumors that have metastasized but adds the risk of turning healthy cells into cancerous cells. Chemotherapy, a third approach to treating cancer, generally carries fewer risks of secondary cancers and can also treat metastasized diseases. Chemotherapies are applicable for many types of cancer because they generally target rapidly dividing cells, which is a hallmark of many cancerous cells. However, chemotherapies aren’t very specific, since the cells that grow hair and the intestinal lining are also rapidly dividing and can also be damaged by the drugs used in chemotherapy.

These three treatment options and combinations thereof have constituted the anti-cancer arsenal for decades, and have often been a one-size-fits-all approach. Targeted therapy, which came on the scene in the late 1990’s, tries to get away from the one-solution paradigm by using cancer drugs specific to a person’s body and cancer. These, though, often lead to the development of drug-resistant tumors. For each therapeutic option, there are trade-offs between efficacy and patient safety. The uses and limitations of different kinds of cancer therapy are listed in Table 1. In addition to these traditional modes of therapy, the last few decades have seen the rise of a promising new option: cancer immunotherapy.

Table 1

Therapy	How does it work?	Side Effects	Limitations
Surgery (cut-and-kill)	Surgically remove the tumor	Removal of healthy surrounding tissue, complications from surgery	Cannot target metastasized cancers
Radiation	Damages the DNA of cancerous cells	Damage to healthy cells resulting in more cancerous cells	Expensive in the long-term
Chemotherapy	Targets rapidly dividing cells (mostly cancer cells)	Hair loss, intestinal damage, nausea	Cancer cells develop resistance to chemotherapy, not specific
Targeted Therapy	Targets proteins required for cancer growth	Liver problems, diarrhea, skin rash	Cancer cells develop resistance
Immunotherapy	Uses our immune system against cancer	Autoimmune effects	Tailored and expensive

Cancer Immunotherapy

For decades, immunotherapy, or the idea of tasking our own immune systems with the goal of killing cancer cells, seemed like science fiction – but in recent years, advances in basic and translational research have brought immunotherapies to the clinic. Current immunotherapies comprise three different therapeutic approaches: adoptive T cell transfer, cancer vaccinations, and checkpoint blockade. Checkpoint blockade takes advantage of the inherent self-regulation of our immune systems and is one of the best-studied forms of cancer immunotherapy, successfully being used to treat melanoma and non-small cell lung cancer.

Checks and balances

Like many other types of cancer treatments, checkpoint blockade therapy was created by observing and copying natural biological processes at play in our immune systems. This complex system is made of many different types of cells whose primary job is to detect and attack foreign pathogens such as bacteria and viruses. For example, when an infection is detected, a type of immune cell called a killer cell becomes activated. The job of killer immune cells is to rapidly grow and divide in order to attack and kill the invading pathogen. Although this process is necessary to protect our bodies from infection, it is also inherently dangerous. When killer cells are activated for prolonged periods of time, they may begin to attack not only the invading pathogen, but also a person’s own healthy tissue, resulting in autoimmune disorders. To avoid this danger, the immune system comes equipped with a series of regulatory, or checkpoint, mechanisms. These regulatory checkpoints function to de-activate the immune system and are vital to prevent autoimmunity (Figure 1).

Checkpoints: Removing the breaks

Immune checkpoint mechanisms are enacted by a group of protein molecules that sit on the surface of immune cells. When it is time to turn off the immune response, these proteins aid in transmitting the off signal to killer cells. An example of this is a protein called PD-L1, which sits on the surface of regulatory cells. PD-L1 binds a protein on killer immune called PD-1, similar to puzzle pieces fitting together (Figure 2). When PD-L1 on regulatory cells meets PD-1 on killer cells, the killer cells stop growing and attacking, decreasing the immune response. This regulation is a normal and invaluable facet of our immune systems.

In addition to attacking foreign pathogens, killer immune cells can also recognize and kill many types of cancer cells. To avoid this immune attack, cancer cells can co-opt immune checkpoints to escape immune detection, taking advantage of the built-in switches to turn the immune system off. For example, many cancer cells inappropriately have PD-L1 protein, allowing them to deactivate the killer immune cells trying to attack them. This allows the cancer cells to evade immune attack and to survive in the vicinity of killer immune cells. Checkpoint blockade therapy, which won the Nobel prize in 2018, works by either blocking the checkpoint receptor on immune cells, or by blocking the signaling PD-L1 on cancer cells (Figure 3).

For checkpoint blockade therapy, scientists can engineer types of proteins called antibodies that specifically and strongly bind to PD-1, preventing it from binding to PD-L1 and thus preventing the immune system from turning off. Immune cells can then more effectively kill cancer cells. Checkpoint blockade therapy is most effective against cancers that have lots of PD-L1 (the off signal), however this can be different for each kind of cancer and each person. For some cancers, blocking PD-1 is effective, while for other cancers, a combination therapy that includes antibodies that bind to other immune receptors is more effective. Checkpoint blockade can also be used in combination with other therapies (like those in Table 1).

The next wonder therapy?

Despite its success in treating certain cancers, checkpoint therapy is not perfect, and one of the major side effects of checkpoint blockade therapy is autoimmune effects on other organs. Because checkpoints are natural mechanisms that turn off the immune response, blockading these checkpoints through therapeutic intervention can destabilize a delicate system of checks and balances. Specifically, by blocking the PD-L1/PD-1 interaction, killer immune cells remain activated and may attack healthy cells, resulting in autoimmunity. This is minimized in cancers where there are many mutations, or changes, which differentiate cancer cells from healthy cells and make them more recognizable to killer immune cells. These cancers with a high number of mutations are also the ones where checkpoint blockade therapy seems to be the most effective, including melanoma and non-small cell lung cancer. Checkpoint blockade provides an answer to the specificity and toxicity problem only for certain kinds of cancer, and more research is needed to make it a more widely effective therapy.

While chemotherapy, radiation, and surgery are still widely used against cancer, immunotherapy is a rapidly growing therapeutic option with ongoing clinical trials against many different types of cancers. The resemblance of cancers cells to healthy cells ensures that toxicity will almost always be an issue, but increasing specificity reduces damage to healthy cells. Cancer immunotherapy moves us further toward increased specificity, benefitting patients by reducing side effects and increasing treatment options.

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Apurva Govande is a 3rd year PhD candidate in the Program in Virology at Harvard University.

Rebecca Clements is a third-year Ph.D. candidate in the Biological and Biomedical Sciences program at Harvard. You can find her on Twitter as @clements_becca.

For more information:

• To learn more about cancer immunotherapy, read this.
• This is a great summary about what’s new in cancer immunotherapy research.
• For more about antibodies and cancer, read this.

This article is part of our SITN20 series, written to celebrate the 20th anniversary of SITN by commemorating the most notable scientific advances of the last two decades. Check out our other SITN20 pieces!