Injured tumor cells activate immuno-oncology drugs to combat breast cancer and melanoma in mice

Breast Cancer Cells
MIT's approach hinges on immunogenic cell death, a process by which dying tumor cells send signals that wake up the immune system. (National Cancer Institute)

The quest to make immune-boosting treatments more widely applicable in cancer has resulted in several combination strategies intended to improve the effectiveness of immuno-oncology drugs like checkpoint inhibitors. Scientists at the Massachusetts Institute of Technology are proposing a new combination strategy—one that capitalizes on signals sent by injured tumor cells to the immune system.

Scientists at the MIT Center for Precision Cancer Medicine developed a method for removing tumor cells, treating them with chemotherapy and then combining them with checkpoint-inhibiting drugs. In mouse models of melanoma and breast cancer, the technique eliminated 40% of tumors, they reported in Science Signaling.

The approach hinges on immunogenic cell death, a process by which dying tumor cells send signals that wake up the immune system. The MIT researchers started by treating tumor cells with different types of chemotherapy, then adding immune cells called dendritic cells, followed later by T cells.

They discovered that chemotherapy didn’t seem to help the T cells kill cancer. And surprisingly, low doses of chemo that injured many cells without killing them were more effective than high doses that killed off scores of tumor cells.

Turns out, the cells that were injured by chemo but not yet dead were stimulating the immune system to attack the cancer, the MIT researchers explained. And the drugs that damaged the DNA of tumor cells were the most effective at prompting T cells to destroy both the injured cells and nearby tumor cells.

“Our findings fit perfectly with the concept that ‘danger signals’ within cells can talk to the immune system,” a controversial theory that dates back to the 1990s, said Michael Yaffe, professor and director of the MIT Center for Precision Cancer Medicine, in a statement.

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The researchers treated tumor cells with the DNA-damaging chemo drug etoposide, injected them directly into tumors in mice, and then gave the animals checkpoint inhibitors. That increased the population of cancer-targeting immune cells, leading to tumor shrinkage, they reported.

When the animals that saw their tumors completely disappear were re-challenged with cancer later, no new tumors appeared, “indicating that the injured cell adjuvant treatment induced durable antitumor immunological memory,” the researchers wrote in the study.

Combinations of chemotherapy and checkpoint inhibitors are making their way to the front of the line in the treatment of some tumors. The standard of care in non-small cell lung cancer (NSCLC) is Merck’s PD-1 inhibitor Keytruda plus chemotherapy. And now another combination could threaten Merck’s lead in that market: PD-1 inhibitor Libtayo, from Sanofi and Regeneron, with chemotherapy.

In August, Sanofi and Regeneron stopped a pivotal trial of the combination after an interim analysis showed that Libtayo plus chemo cut the risk of death by 29% over chemo alone. The combo also extended survival by a median of 21.9 months, while chemo alone added just 13 months.

Other novel approaches to improving immuno-oncology are under investigation. Earlier this month, scientists at Yale spinout Cybrexa reported that a peptide-drug conjugate that capitalizes on the acidic environment around cancer cells improved the potency of checkpoint inhibitors in mouse models of colon cancer.

The MIT team argued that new approaches to improving immuno-oncology treatments are needed, given that more than half of patients in the successful Keytruda trials still saw their cancers progress. The three-part approach they described in the new study could be promising for patients with tumors that are easy to inject with the damaged cancer cells, they added.