By combining chemotherapy, tumor injury and immunotherapy, researchers show that the immune system can be reactivated to destroy tumors in mice.
Immunotherapy is a promising strategy for treating cancer by stimulating the body’s immune system to destroy tumor cells, but it only works for a handful of cancers. MIT researchers have now discovered a new way to jump-start the immune system to attack tumors, which they hope could allow immunotherapy to be used against more types of cancer.
Their new approach involves removing tumor cells from the body, treating them with chemotherapy drugs, and then placing them back into the tumor. When given with drugs that activate T cells, these injured cancer cells appear to act as a distress signal that prompts the T cells to act.
âWhen you create cells that have DNA damage but are not killed, under certain conditions these living and injured cells can send a signal that awakens the immune system, âsays Michael Yaffe, science professor David H. Koch, director of the MIT Center for Precision Cancer Medicine. , and Fellow of the Koch Institute for Integrative Cancer Research at MIT.
In studies on mice, researchers found that this treatment could completely eliminate tumors in almost half of the mice.
Yaffe and Darrell Irvine, who is Professor Underwood-Prescott with appointments in the Departments of Biological Engineering and Materials Science and Engineering at MIT, and Associate Director of the Koch Institute, are the lead authors of the study, which appears today ‘hui in Scientific signage. MIT postdoctoral fellow Ganapathy Sriram and Lauren Milling PhD ’21 are the lead authors of the article.
Activation of T lymphocytes
One class of drugs currently used for cancer immunotherapy are checkpoint blocking inhibitors, which inhibit T cells that have become “depleted” and unable to attack tumors. These drugs have been successful in treating a few types of cancer, but do not work against many others.
Yaffe and his colleagues tried to improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs, in the hopes that the chemotherapy might help boost the immune system to kill tumor cells. This approach is based on a phenomenon known as immunogenic cell death, in which dead or dying tumor cells send signals that attract the attention of the immune system.
Several clinical trials combining chemotherapy and immunotherapy drugs are underway, but little is known to date about how best to combine these two types of treatment.
The MIT team began by treating cancer cells with several different chemotherapy drugs at different doses. Twenty-four hours after treatment, the researchers added dendritic cells to each box, followed 24 hours later by T cells. Then, they measured how well the T cells were able to kill cancer cells. To their surprise, they found that most chemotherapy drugs did not help them much. And those who helped seemed to work best at low doses that didn’t kill a lot of cells.
The researchers later realized why this was so: it was not dead tumor cells that boosted the immune system; instead, the critical factor was the cells that were injured by chemotherapy but still alive.
“This describes a new concept of immunogenic cell injury rather than immunogenic cell death for the treatment of cancer,” Yaffe explains. “We have shown that if you process tumor cells in a box, when you inject them directly back into the tumor and give checkpoint blocking inhibitors, the living and injured cells are the ones that wake up the immune system.”
The drugs that seem to work best with this approach are drugs that cause DNA damage. Researchers have found that when DNA damage occurs in tumor cells, it activates cellular pathways that respond to stress. These pathways send distress signals that prompt T cells to take action and destroy not only injured cells, but any nearby tumor cells as well.
“Our results fit perfectly with the concept that ‘danger signals’ in cells can communicate with the immune system, a theory pioneered by Polly Matzinger at the NIH in the 1990s, although it is still not universally accepted,” explains Yaffe.
Removal of the tumor
In studies of mice with melanoma and mammary tumors, researchers showed that this treatment completely eliminated tumors in 40 percent of the mice. What’s more, when researchers injected cancer cells into these same mice several months later, their T cells recognized them and destroyed them before they could form new tumors.
The researchers also tried injecting DNA-damaging drugs directly into the tumors, instead of treating cells outside the body, but found that was not effective because the chemotherapy drugs also caused damage. T cells and other immune cells near the tumor. In addition, injection of injured cells without checkpoint blocking inhibitors had little effect.
âYou have to present something that can act as an immunostimulant, but you also have to release the pre-existing block on the immune cells,â says Yaffe.
Yaffe hopes to test this approach in patients whose tumors have not responded to immunotherapy, but more studies are needed first to determine which drugs, and at what doses, would be most beneficial for different types of tumors. . Researchers are also studying in more detail how damaged tumor cells stimulate such a strong T cell response.
Reference: âResponse to DNA Damage in Living Tumor Cells Promotes Antitumor Immunityâ by Ganapathy Sriram, Lauren E. Milling, Jung-Kuei Chen, Yi Wen Kong, Brian A. Joughin, Wuhbet Abraham, Susanne Swartwout, Erika D. Handly, Darrell J. Irvine and Michael B. Yaffe, October 19, 2021, Scientific signage.
DOI: 10.1126 / scisignal.abc4764
The research was funded, in part, by the National Institutes of Health, the Mazumdar-Shaw International Oncology Fellowship, the MIT Center for Precision Cancer Medicine, and the Charles and Marjorie Holloway Foundation.