Using CRISPR to turn cancer cells against themselves

Taking healthy immune-boosting T cells from patients and engineering them to recognize and kill cancer is a well-established approach now, with the success of Gilead’s Yescarta and Novartis’ Kymriah. But researchers at Brigham and Women's Hospital have a different idea for creating cancer-killing cells—and it involves modifying tumor cells instead of T cells.

The team is using CRISPR gene editing to modify cancer cells so they can home in on tumors and deliver therapies to them. So far, they’re getting promising results in animal models of breast and brain cancer, they reported in the journal Science Translational Medicine.

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The researchers developed two different types of cells. The first were pre-engineered tumor cells that could be used off-the-shelf by matching them to patients’ “HLA phenotypes,” or the proteins that regulate their immune systems. The second were patient-specific tumor cells that were edited with CRISPR. During the editing process, the researchers inserted therapeutic molecules to induce the killing of tumor cells.

Both approaches were designed to capitalize on the natural ability of cancer cells to track down other cells like them—including tumor cells that have spread beyond the original disease site. The researchers believe this approach could help combat one of the biggest challenges in cancer care, which is to treat tumors in hard-to-reach places.

They tested both types of cells in mouse models of brain cancer and breast cancer that had metastasized to the brain. The researchers reported that the engineered cells migrated to tumor cells and killed both recurrent and metastatic cancer. The treatments also extended the lives of the animals. What’s more, the cells were engineered with a “kill switch,” so they could be inactivated after the treatment. Using PET scans, the researchers confirmed the kill switch worked.

“With our technique, we show it is possible to reverse-engineer a patient's own cancer cells and use them to treat cancer,” said co-author Khalid Shah, Ph.D., director of the Center for Stem Cell Therapeutics and Imaging in the BWH Department of Neurosurgery. “We think this has many implications and could be applicable across all cancer cell types."

Efforts to develop new engineered-cell approaches to oncology range from testing entirely new technologies to finding ways to improve CAR-T treatments like Yescarta and Kymriah. CAR-T approaches have been embraced because of their effectiveness in blood cancers, but they’ve proven difficult to apply to other tumor types, and they can cause dangerous immune reactions. 

In their journal article, the Brigham and Women's authors noted that other studies have explored the use of cancer cells as treatments, but the need to limit their activity for safety reasons caused the cells to be eliminated or to "die before reaching the primary or metastatic tumor cells,” they wrote. They believe their therapy can induce apoptosis—or programmed cell death—in tumors before the kill switch eliminates the engineered cells.

The researchers envision that the therapy could be translated to people by removing patients’ tumors, engineering the cancer cells outside the body and then readministering the cells via a route that would depend on the type of the cancer and what stage it’s in, they wrote. “These cells would result in killing of residual, invasive, and metastatic tumor deposits with the ultimate goal of improving outcomes.”