Using cancer to fight cancer might seem counterintuitive, but there’s method to the apparent madness and, according to proof-of-principle animal experiments reported in Science Translational Medicine today (July 11), it works. Tumor cells engineered to secrete anticancer agents yet resist self-destruction can be used to kill tumors in mice and then, in a fate befitting this act of betrayal, off themselves.
“This is an interesting study showing that genetically-engineered autologous cancer cells can be exploited as a sort of Trojan horse for delivering TRAIL, a pro-apoptotic agent, to tumors,” oncologist Angelo Corti of the Vita-Salute San Raffaele University in Milan, Italy, who was not involved in the study, writes in an email to The Scientist. “This novel approach undoubtedly represents an important step ahead in translational cancer research.”
TRAIL—or, tumor necrosis factor-related apoptosis-inducing ligand—is an antitumor agent identified in mammals that can induce cell death in a variety of cancer cells and yet leaves healthy cells relatively unscathed. “For TRAIL-sensitive tumors, TRAIL is an excellent therapeutic agent. . . . It’s very potent,” says cancer researcher Gen Sheng Wu of Wayne State University School of Medicine in Detroit who also did not participate in the research. However, he adds, TRAIL has not translated well clinically because of the protein’s short half-life and thus the difficulty of delivering a sufficient and sustained dose to the tumor.
Engineered cells that produce TRAIL on site may be a solution to this problem, and neurologist Khalid Shah of Harvard Medical School and colleagues considered the cancer cells themselves as potential candidates for the job. Using the very cells they aimed to kill “may seem a paradoxical approach,” writes Corti, but there’s a number of reasons the idea might work.
For one, cancer cells are easy to obtain during surgery to remove the tumor and easy to grow in the laboratory, says Wu. The cells would also be derived from the patient, “so there’s no immunorejection.” And, of key importance, tumor cells have a natural homing ability, Wu explains. Aside from disseminating around the body during metastasis, cancer cells can also return to and recolonize their tumors of origin—a phenomenon known as tumor self-seeding.
To test out the idea, Shah and colleagues engineered human glioblastoma cells to both secrete TRAIL and to be resistant to the protein, by removing the cells’ ability to express the TRAIL surface receptors. Of course, says Shah, deploying cancer cells for therapy “is a double-edged sword” because they could spawn new tumors themselves. To prevent this possibility, the team also built in a suicide system—an enzyme that converts a relatively harmless medication into a locally acting, toxic substance, eliminating the therapeutic cells when the mouse is given the drug.
The researchers delivered the engineered cells a small distance from autologous tumors developed in mice and found evidence of cell migration toward the cancer that resulted in diminished tumor size and improved survival of the animals when compared with controls that received equivalent cells unable to secrete TRAIL.
Although autologous cells would be ideal for clinical translation, says Shah, his team also created off-the-shelf, allogenic therapeutic cells using a TRAIL-insensitive gliobastoma cell line, which was also effective at treating tumors in mice. In a clinical setting, such cell lines could be HLA matched to patients to improve the chances of immunocompatibility.
“This is an interesting manuscript that builds upon previous work exploring the biological phenomena of tumor self-seeding enabling self-targeting with genetically engineered tumor cells,” Renata Pasqualini of Rutgers Cancer Institute of New Jersey who was not involved in the research writes in an email to The Scientist. However, “the translational potential really depends on safety being demonstrated as further studies are performed,” she says.
In addition to safety testing, “the use of multiple vectors and of labor-intensive technologies to produce this therapeutic agent may represent another limitation for its clinical development,” writes Corti, “Nevertheless, the results of this study, which provide an important proof-of-principle, may burst further studies to make this process simple and safe and to finally exploit cancer cells as novel vehicles of therapeutic agents.”
C. Reinshagen et al., “CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors,” Science Translational Medicine, 10:eaao3240, 2018.