What’s New in Immunotherapy?

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Issue 5, Volume 112

By Arin Faruque 

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Currently, the most promising development in the war against cancer comes from immunotherapy, a type of treatment that stimulates the immune system to recognize and fight cancer cells. Cancer cells that were previously able to evade the immune system now stand out and are “marked” in this treatment, eliciting an immune response. The most common immunotherapy used right now is CAR T-cell therapy, where genetically altered T-cells are inserted into cancer patients who have already undergone chemotherapy. One new take to this comes from a team of researchers at MIT. In their approach, they incorporate the chemotherapy aspect, but base their overall treatment outside of the body by removing tumor cells rather than immune cells from the body and reinserting them after treating them with specific drugs to incite an immune response.

The first of these drugs are known as immune checkpoint inhibitors, which counter the inability of T-cells, the body’s defense against foreign particles, to attack cancer cells. Checkpoint proteins on the surface of the cells can either inhibit or enable immune response. The binding of the checkpoint proteins, most notably the proteins PD-1 and PD-L1 on the T-cell and tumor cell, respectively, prevents the T-cell from attacking the tumor cell. Checkpoint inhibitors prevent the binding of these proteins, thus allowing the T-cell to attack the cancerous cell. However, immune checkpoint inhibitors only work on some types of cancer. To further improve the immune system’s ability to target tumor cells, researchers combined the immune checkpoint inhibitors with traditional cytotoxic chemotherapy drugs used to kill rapidly growing cells. They based their thinking on a phenomenon called immunogenic cell death, where injured or dead tumor cells alarm the immune system. However, researchers soon realized that it was only the injured tumor cells that triggered the response.

In their first trials, the team tested different types of chemotherapy drugs on the cancer cells and measured the corresponding T-cell response. 24 hours after treating the cancer cells with the drugs, the researchers added dendritic cells—which present antigens to T-cells and activate them—to each dish, followed by the T-cells themselves 24 hours later. After recording the effectiveness of killing cancer cells with T-cells, researchers found that the chemotherapy drugs did not have the impact they expected: only dishes with low doses of the drugs that only injured the cells had notable improvement. The researchers sought an explanation for this result and found that drugs that cause DNA damage were the most effective because of their connection to our cellular stress mechanism. DNA-damaged cells release distress signals that call T-cells into action, which destroy both the damaged cells and surrounding tumor cells.

After testing these observations in mice with melanoma, a type of skin cancer, and breast cancers, they found that the treatment had killed all tumors in 40 percent of the mice. Additionally, when the researchers re-inserted cancer cells into the same mice several months later, their T-cells remarkably identified and killed those cells before they could divide and form new tumors.

These results contribute to the growing field of immunotherapy and its use as a substitute for more widely used methods such as chemotherapy and radiation treatment, which have unpleasant systemic side effects. Chemotherapy and radiation are not precise as they target fast-dividing cancerous and non-cancerous cells, leading to side effects like hair loss and nausea as hair cells and stomach cells divide quickly. Immunotherapy, on the other hand, identifies and targets specific cancer cells to remove this risk. This allows immunotherapy to be used in a greater variety of cancer therapies, such as a new immunotherapy treatment for pancreatic cancer—the most deadly cancer—that is set for clinical trials later this year. This treatment, which manipulates the PD-1 and PD-L1 system of T-cells with a specific combination of drugs to enable an immune response, is one of many arising targeted immunotherapies to treat various kinds of cancers.

Though these results are exciting, more extensive research is needed to determine the most effective types of drugs and their optimal dosages. Many current immunotherapy drugs are extremely expensive, with some costing up to $475,000 per year. This places more importance on the development of this combined approach that may offer more affordable cancer treatment. The field of immunotherapy remains promising as new, innovative approaches to treating a historically incurable disease turn its application into more practicality.