CRISPR Combats Cancer
Recently, Gilead’s Yescarta and Novartis’ Kymriah took healthy immune-boosting T cells from patients and engineered them to recognize and destroy cancer. Now researchers at Brigham and Women's Hospital are creating cells that kill cancer by modifying tumor cells instead of T cells, according to Arlene Weintraub in Fierce Biotech.
Using CRISPR gene editing to modify cancer cells, the team plans to focus on tumors and deliver therapies to them. As of the publication of the article, the researchers are obtaining promising results in animal models of breast and brain cancer.
CRISPR technology -- a simple but powerful tool for editing genomes -- enables researchers to alter DNA sequences easily and modify gene function. Applications include fixing genetic defects, treating and preventing the spread of diseases and enhancing crops.
"CRISPR" stands for "clusters of short, regularly interspaced palindromic repeats." The specialized region of DNA has two distinct characteristics: the presence of nucleotide repeats and spacers. Repeated sequences of nucleotides, the building blocks of DNA, are distributed throughout a CRISPR region. Spacers are pieces of DNA interspersed among these repeated sequences. In bacteria, the spacers come from viruses that had attacked the organism. As a bank of memories, they allow for bacteria to recognize the viruses and fight off future attacks.
As the researchers reported in the journal Science Translational Medicine, they developed two different types of cells. Their pre-engineered tumor cells could be used off the shelf by matching them to patients’ “HLA phenotypes,” the proteins regulating their immune systems. They edited patient-specific tumor cells with CRISPR. While the cells were being edited, the scientists added therapeutic molecules to advance the killing of tumor cells.
Both of these approaches attempted to maximize the natural ability of cancer cells to hunt down other cells like them, such as tumor cells that have metastasized beyond the original disease site. The scientists think this approach could assist in fighting one of the biggest obstacles in cancer care: treating tumors in hard-to-reach places.
The researchers tested both types of cells in mouse models of brain cancer and breast cancer that had metastasized to the brain and reported that the engineered cells migrated to tumor cells and killed both recurrent and metastatic cancer. Additionally, the treatments extended the lives of the animals. Engineered with a “kill switch,” the cells could be inactivated after the treatment. Using PET scans, the researchers confirmed that the kill switch was effective.
According to co-author Khalid Shah, Ph.D., director of the Center for Stem Cell Therapeutics and Imaging in the BWH Department of Neurosurgery, “With our technique, we show it is possible to reverse-engineer a patient's own cancer cells and use them to treat cancer. We think this has many implications and could be applicable across all cancer cell types."
Attempts to develop new engineered-cell approaches to oncology range from testing entirely new technologies to finding ways to improve CAR-T treatments such as Yescarta and Kymriah. CAR-T approaches are effective in dealing with blood cancers, but they are hard to apply to other tumor types, and they can cause dangerous immune reactions.
The Brigham and Women's authors noted in their article that other studies have explored the use of cancer cells as treatments. They explained that 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 believe their therapy can induce apoptosis, programmed cell death, in tumors before the kill switch eliminates the engineered cells.
The researchers believe that the therapy could be translated to people by removing patients’ tumors, engineering the cancer cells outside the body and then readministering the cells by a route that would depend on the type of the cancer and its stage. As they explained, “These cells would result in killing of residual, invasive, and metastatic tumor deposits with the ultimate goal of improving outcomes.”