Biomedical researchers at Vanderbilt University have created "cellular soldiers" that use the body's innate defenses to eliminate cancer cells dispersed during surgery. When used perioperatively, the attack cells kill stray cancer cells and keep them from forming metastases.
If testing proceeds on track and current discussions with a pharmaceutical company progress as expected, the researchers could begin testing the technology in human volunteers within 18 months, lead researcher Michael King, professor of engineering and chair of the biomedical engineering department at Vanderbilt, told BioWorld.
To make the attack cells, King and his team attach TNF-related apoptosis-inducing ligand (TRAIL) and adhesion receptor E-selectin proteins to the surface of lipid nanoparticles. Once injected, the nanoparticles adhere to white blood cells. The weaponized leukocytes then kill cancer cells in the bloodstream.
"TRAIL-coated leukocytes eliminate about 70 percent of cancer cells from blood within the first two hours of testing, and that result is pretty consistent across many types of human cancers," King said.
In animal studies, the researchers have found that administering one dose two days before surgery, followed by a dose on the day of surgery and a third three days later gives the best results. "The therapeutic tends to circulate for about three days before washing out," King noted. "These schedules could change in future human testing, of course."
Effective in triple-negative breast cancer
In a study published in Science Advances, the team presented the results of the technique when applied to a mouse model of triple-negative breast cancer.
"Metastasis remains the most critical condition limiting cancer patient survival, and the development of effective treatments against metastatic cancers, especially triple-negative breast cancer (TNBC), is among the greatest challenges in current experimental and clinical cancer research," they noted.
TNBC is a typically aggressive and mutationally highly heterogenous form of breast cancer that affects 10% to 20% of all women with the disease. As the cancer does not respond to hormone or anti-HER2 therapies, patients have fewer treatment options than those who develop other types of breast cancer. So far, targeted therapies have not reached phase III trials for TNBC, leaving chemotherapy the only currently validated treatment.
While surgery to remove the primary tumor is typically recommended, surgery itself can disperse cancer cells into the bloodstream and may cause an inflammatory response that favors relapse or metastasis.
Injecting the altered leukocytes reduces the risk of metastases by delivering a one-two punch to any cancer cells disrupted during surgery. The recombinant human E-selectin protein that attaches the injected lipid to the white blood cell also attracts cancer cells that express E-selectin ligands. TRAIL then binds to the cells' death receptors, killing them.
In the current study, the researchers injected mice with 4T1-luc cells which caused them to develop a highly invasive, rapidly metastasizing breast cancer similar to TNBC. The mice injected with the TRAIL and E-selectin-coated lipids had notably longer median survival than those who were injected with empty lipids or the soluble form of TRAIL – 51 days vs. 45 days and 40 days, respectively. Two of the mice injected with the investigational combination remained alive at 250 days.
The researchers also determined that mice injected with the treated lipids also had fewer disseminating metastatic cells after each treatment. While the other two groups experienced an approximately fourfold increase in disseminating cancer cells during the study, those injected with the coated lipids had a 12% reduction.
Range of potential use in cancers
"Triple-negative breast cancer was an attractive target for us due to its difficulty of treatment, but our laboratory tests have determined that the approach is also quite effective in prostate cancer, colon cancer, and other types of cancer such as lung and ovarian," King explained. "Most of our data with these types of cancer come from experiments with blood samples collected from late-stage cancer patients."
The team is also exploring other mechanisms for producing these "cellular soldiers," which could be used to prevent metastases over the longer term.
"My lab is currently experimenting with more long-lived therapeutics, in which the body's blood cells are genetically engineered to produce their own TRAIL protein," King noted. "A gene therapy approach such as this could provide ongoing protection for months or even years."
The altered leukocytes also attack tumors and could be used to reduce primary tumors as well. "In our animal experiments, we have found that the TRAIL-coated leukocytes do not just protect the blood circulation, they also enter into solid tumors to slow their growth," King said. "In one surprising instance, we found that the necrotic or dead core of the primary tumor increased in size after a single TRAIL liposome injection."