New cancer treatment may reawaken the immune system

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Immunotherapy is a promising strategy for treating cancer by stimulating the body’s own immune system to destroy tumor cells, but it works for only a handful of cancers. Researchers at MIT have discovered new ways to jump start the immune system and attack tumors. We hope that this will allow immunotherapy to be used for more types of cancer.

For their novel approach, tumor cell The body is treated with chemotherapeutic drugs and returned to the tumor. These are injured when delivered with drugs that activate T cells cancer The cells appear to act as distress signals that drive T cells into action.

“If you make cells that have DNA damage but are not killed, the damaged cells can signal and awaken if they are alive under certain conditions. Immune system“Michael Jaffe, Professor of Science, David H. Koch, Director of the MIT Center for Precision Cancer Medicine, and a member of the Koch Institute for Integrated Cancer at MIT.

In a mouse study, researchers found that this treatment could completely eliminate tumors in almost half of the mice.

Professor Underwood-Prescott and Deputy Director of the Koch Institute, Jaffe and Darrell Irvine, appointed to the Department of Biotechnology and Materials Science and Engineering at MIT, today Scientific signaling.. MIT Postdocs Ganapathy Sriram and Lauren Milling Ph.D. ’21 are the lead authors of the treatise.

T cell activation

One class of drugs currently used in cancer immunotherapy is a checkpoint block inhibitor that releases the brakes on T cells that are “depleted” and unable to attack tumors. These drugs have been shown to be successful in treating some types of cancer, but they are ineffective against many other types of cancer.

Yaffe and his colleagues hope that chemotherapy will help stimulate the immune system to kill tumor cells and improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs. I tried. This approach is based on a phenomenon known as immunogenic cell death. In this phenomenon, dead or dying tumor cells send signals that draw the attention of the immune system.

Several clinical trials are underway that combine chemotherapeutic and immunotherapeutic agents, but little is known about the best way to combine these two types of treatment.

The MIT team began by treating cancer cells with several different chemotherapeutic agents in different doses.Twenty-four hours after treatment, the researchers added Dendritic cells Each dish is followed by T cells after 24 hours. Next, they measured how well T cells were able to kill cancer cells. Surprisingly, they found that most chemotherapeutic drugs were not very useful. And the ones that helped seemed to work best at low doses that didn’t kill many cells.

Researchers later understood why this was the case. It was not the dead tumor cells that stimulated the immune system. Instead, a key factor was cells that were damaged by chemotherapy but still alive.

“This explains a new concept of immunogenic cell death, not immunogenic cell death for the treatment of cancer,” says Yaffe. “When we treated the tumor cells with a dish, we showed that when the tumor cells were injected directly into the tumor and given a checkpoint block inhibitor, the live damaged cells awakened the immune system again.”

The drugs that appear to be most effective with this approach are those that cause DNA damage. Researchers have found that DNA damage in tumor cells activates cell pathways that respond to stress. These pathways send distress signals, stimulate T cells to take action, and destroy not only damaged cells but also nearby tumor cells.

“Our findings are in perfect agreement with the notion that intracellular” danger signals “can communicate with the immune system. This is a theory pioneered by Polly Matzinger at NIH in the 1990s, but it has not yet been widely accepted, “says Yaffe.

Tumor removal

In a study of mice with melanoma and breast tumors, researchers showed that this treatment completely eliminated the tumor in 40 percent of the mice. In addition, when researchers injected cancer cells into these same mice a few months later, their T cells recognized them and destroyed them before they formed new tumors.

Researchers also tried to inject DNA-damaging drugs directly into the tumor instead of treating cells outside the body, but found that this was not effective. Chemotherapy drug It also harmed T cells and other immune cells near the tumor. Also, injecting damaged cells without a checkpoint block inhibitor had little effect.

“We need to present something that can act as an immunostimulant, but we also need to release the existing block of immune cells,” says Yaffe.

Yaffe wants to test this approach in patients whose tumors have not responded to immunotherapy, but first to determine which drug and which dose are most beneficial to different types of tumors. Further research is needed.Researchers are also investigating more details about how the injured were injured. Tumor cells Stimulates such a strong T cell response.

Studies point to strategies for overcoming immunotherapy resistance in colorectal cancer

For more information:
The damaging response to DNA damage in living tumor cells promotes anti-tumor immunity, Sriram et al. , Science.signal.. 14, eabc4764 (2021). DOI: 10.1126 / scisignal.abc4764

Quote: New cancer treatment is available from on October 19, 2021 (October 19, 2021) May wake up again

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