‘Masked’ cancer drug stealthily trains immune system to kill tumors while sparing healthy tissues, reducing treatment side effects


Numerous cancer therapies are well-known for being brutal on the body. Drugs frequently assault both tumor cells and healthy cells, leading to a wide range of adverse effects. Immunotherapies, which support the immune system's ability to identify and combat cancer cells, are similar. They only function in a portion of patients, despite the fact that they have extended the lives of countless others. Less than 30% of breast cancer patients react to one of the most popular types of immunotherapy, according to one research.

What if, however, medications could be developed to target specifically tumor cells while leaving healthy cells unharmed? In order to prevent one potential cancer medication from causing havoc, Jeffrey Hubbell and colleagues at the University of Chicago's Pritzker School of Molecular Engineering has developed a mechanism that "masks" the medicine until it reaches a tumor.

The promise of IL-12

Proteins called cytokines have the ability to control how the immune system reacts to dangers. They accomplish this, among other things, by turning on killer T cells, a subset of white blood cells that may go after cancer cells. Cytokines hold great promise as cancer therapies because they may teach the immune system to eradicate malignancies.

Interleukin-12, sometimes known as IL-12, is one such cytokine. IL-12 was discovered more than 30 years ago, but because to its serious adverse effects, such as liver damage, it is still not an FDA-approved medication for cancer patients. This is partially due to the fact that IL-12 tells immune cells to make a lot of harmful inflammatory chemicals, which can harm the body.

Since then, researchers have been striving to reengineer IL-12 such that it still has the same anticancer effects but is more acceptable.

Masking the killer

"My colleagues and I took use of one of the primary distinctions between healthy and malignant tissue: an overabundance of growth-promoting enzymes in malignancies, to produce a safer variant of IL-12. Because they multiply so quickly, cancer cells overproduce particular enzymes that enable them to infiltrate neighboring healthy tissue and spread to other areas of the body. Healthy cells create fewer of these enzymes and develop at a much slower rate", says Jeffrey Hubbell.

"Our findings showed that only tumor samples were able to lift the cap when we applied these disguised IL-12 molecules to both healthy and tumor tissue provided by melanoma and breast cancer patients. This suggested that masked IL-12 could be able to trigger an effective immune response against malignancies without endangering healthy organs.

We next measured liver damage indicators in mice to determine the safety of masked IL-12. In mice given masked IL-12 over a period of many weeks, we discovered that immune-related adverse effects usually associated with IL-12 were conspicuously missing, indicating better safety.

Our masked IL-12 led to a 90% cure rate in breast cancer models, but treatment with a checkpoint inhibitor, a typical immunotherapy, only led to a 10% cure rate. Masked IL-12 demonstrated a cure rate of 100 percent in a colon cancer model.

The modified IL-12 will then be tested on cancer patients as our next step. We think a potential new treatment is on the horizon, even if it will take time to get this exciting breakthrough directly to patients.

In light of this, we "masked" IL-12 by adding a cap to the area of the molecule that typically attaches to and activates immune cells. Only when the cap comes into touch with enzymes that are present around tumors is the cap removed. Once the cap is removed by these enzymes, IL-12 is reactivated and triggers neighboring killer T cells to assault the tumor".

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