Known as the "anti-cancer fighter", CAR-T cells have proven their power in recent years. Three treatments for the treatment of lymphoma or leukemia using T cells have been approved by the US Food and Drug Administration (FDA). Moreover, hundreds of trials have been used to treat other malignancies, including solid tumors. But these cells may soon have companions. Researchers have equipped the same type of cancer homing receptors for other immune "guards" -- natural killer cells and macrophages -- and natural killer cells have made their debut in clinical trials.
The name of CAR-T cells comes from the chimeric antigen receptor (CAR), which helps immune cells target cancer cells. CAR natural killer (CAR-NK) cells are safer, faster to produce, and less expensive, and they may work in the event of a T cell decline. CAR macrophages also have potential advantages, and a company plans to conduct first clinical trials of these cells this year.
Although they are unlikely to replace CAR-T cells, these cancer treatment alternatives "may be a complement to cell therapy," said Katy Rezvani, a hematologist and oncologist at the MD Anderson Cancer Center at the University of Texas at Houston, Texas. She led the first trial of CAR-NK cells in the United States, which began in 2017.
Manufacturing CAR-T cells requires removal of the patient's own T cells and genetic engineering to attack cancer cells carrying specific immunostimulatory molecules or antigens. These cells have achieved impressive results in clinical trials - in one study, they alleviated 83% of children with acute lymphoblastic leukemia. However, some patients who have received chemotherapy or radiation may not have enough T cell supply. These powerful immune warriors may trigger a deadly spread of immune system molecules (cytokines) and attack ordinary somatic cells.
Saar Gill, a hematologist and oncologist at the University of Pennsylvania, says the biggest drawback of CAR-T cells may be that they don't fight well against solid tumors. Tumors reject T cells that are attempting to enter and inhibit the entry of immune cells into and inhibit the production of CAR-T cell-targeting antigens. Researchers are experimenting with several ways to improve the ability of CAR-T cells to fight solid tumors. But scientists say NK cells are an attractive option.
"Natural killer cells are our first line of defense against cancer cells," Rezvani said. They scan other cells in the body and destroy any infected or other abnormal cells, including tumor cells. University of Minnesota transforming immunologist Jeffrey Miller pointed out that researchers have been trying to exploit the anticancer activity of NK cells for more than 20 years. And upgrading them by adding CAR seems to enhance their effectiveness.
For example, earlier this year, Dan Kaufman, a stem cell biologist at the University of California, San Diego, and colleagues reported that in mice, CAR-NK cells are more resistant to ovarian tumors than CAR-T cells and are significantly better than unchanged. NK cells. Mouse experiments have also shown that the use of CAR-NK cells may not have certain side effects of CAR-T cells, such as excessive release of cytokines and nerve damage.
CAR-NK cells may also be less susceptible to tumor attacks. Because NK cells rely on other receptors to recognize tumor cells, not just CAR cells, they can be detected even if the antigens of the tumor change. In addition, Kaufman also pointed out that it is feasible to inject multiple doses of CAR NK cells into patients and use them for tumor treatment, while the cost of CAR-T cells limits patients to a single dose.
The first trials of CAR-NK cells were conducted in China in 2016 for patients with multiple cancers, and preliminary results indicate that these cells are safe. A trial conducted in Europe last year conducted a CAR-NK cell therapy test for patients with brain cancer glioblastoma. In the upcoming MD Anderson clinical trial, patients with B-cell lymphoma will undergo stem cell transplantation and chemotherapy before CAR-NK cell formation, which researchers hope will clear residual cancer cells.
"I think the future of CAR-NK cells is bright, but we are in the early stages," said Mitchell Cairo, a hematologist at Hawthorne's New York Medical School. Another problem that hinders the use of T cells is the source problem: T cells from people other than patients may cause fatal immune complications, ie graft-versus-host disease, which may attack the recipient's own tissues.
However, NK cells from donors do not appear to cause this response. Although it is possible to screen out NK cells from the blood of blood donors, this method is expensive and may cause harm to blood donors. Both MD Anderson trials rely on NK cells isolated from cord blood and then implanted in CAR. The researchers said that the donated cord blood is abundant and that a large number of NK cells can grow from it.
In contrast, there are experiments that produce enough NK cells by extracting cell lines from lymphoma patients. Torsten Tonn, an immunologist at the Technical University in Dresden, Germany, said that although they originated in cancer, they seem to be safe. The Kaufman team is also exploring another possible source of NK cells: induced pluripotent stem cells.
All of these methods may make it unnecessary for CAR-NK cells to be extracted and modified from the cancer patient's own cells. Miller points out that the patient's immune system may eventually repel any foreign NK cells. But before that, Rezvani and other researchers believe that donor NK cells will have time to fight cancer cells, but the question is whether they can persist for long enough to benefit patients.
Like NK cells, macrophages can destroy cancer cells. But the problem is that most macrophages in tumors are "traitors", for example, these macrophages can help tumors by suppressing immune attacks. "Tumors allow macrophages to support growth and turn them into their own minions," Gill said. But he and graduate student Michael Klichinsky found that equipping macrophages with CAR prevented them from changing direction.
