Synthetic antibody–immune cell complex dramatically shrinks blood tumors

NEW ORLEANS—Donated immune cells mixed with a molecule that helps them home in on tumor cells have dramatically shrunk tumors in most of the 22 people with blood cancer who received experimental infusions. The results, reported yesterday at the annual meeting of the American Association for Cancer Research (AACR), are a new twist on cell therapies that harness a patient’s own immune cells to treat cancer. The new treatment is simpler to make than other cell therapies for advanced lymphoma, or cancer of the lymph system, the study’s leaders say.

“It’s an interesting idea,” says hematologist and oncologist Jeffrey Miller of the University of Minnesota, Twin Cities, who was a panelist at the plenary session where the work was presented.

CAR-T cells, immune cells genetically modified to carry a surface protein that helps them home in on cancer cells, are the best known cancer cell therapy. Although approved for some types of leukemia and lymphoma, CAR-T cells can cause serious side effects and must be custom-made from a person’s own T cells.

To craft a potentially gentler, more practical alternative, some researchers are equipping a different type of immune cell, natural killer (NK) cells, with the surface protein. Known as a chimeric antigen receptor (CAR), it binds to a tumor cell surface protein, or marker, that identifies the cell as cancerous. Unlike CAR-T cells, these cells can be harvested from donated blood, either from an adult donor or from umbilical cord blood, and they don’t provoke a dangerous immune response if infused into another person.

But genetically engineering CAR cells is costly and complex. As a shortcut, scientists are devising protein drugs called bispecific antibodies. These antibodies have two arms, one that sticks to a T cell or an NK cell and the other to a tumor marker. When infused into a patient, the antibody bridges the two cells so the immune cell attacks a tumor much like a CAR cell does.

One such bispecific, called AFM13, links NK cells to a marker called CD30 on Hodgkin’s lymphoma cells. But the antibody, produced by biotech company Affimed, hasn’t worked well in patients so far. Hematologist and oncologist Katy Rezvani at MD Anderson Cancer Center and colleagues thought the problem might be with the patient’s own NK cells: They were simply too weak to function, compared with those of a healthy person. So her team tried mixing AFM13 in a lab dish with donated, normal NK cells. They added a cocktail of proteins called cytokines to boost their potency. “It was such a simple idea,” Rezvani says. But the NK cell–antibody complex worked well at shrinking tumors in mice.

They then tested the strategy in 22 people seriously ill with Hodgkin’s lymphoma who had relapsed after many different treatments. The patients first got a few days of chemotherapy to deplete their own NK cells and make room for the donated cells. They next received an infusion of AFM13-coated cells isolated from umbilical cord blood. Because the bispecific antibody falls off the NK cell within a few days, they also got weekly infusions of AFM13. A month later, they received a second dose of the AFM13–NK cell treatment with cells from a different cord blood donor.

The AFM13-dotted NK cells themselves only stick around for about 3 weeks before a person’s immune system eliminates them. “But those 3 weeks are plenty for a good response. We see massive tumor lesions shrinking within a day,” says oncologist Yago Nieto, who presented the work at the AACR meeting. No patients experienced serious side effects, and tumors shrank in 17 of 19 patients who could be evaluated. In the 13 who got the highest of three NK cell doses, tumors disappeared completely in eight cases.

One woman in her 50s was going into hospice and could barely walk when she joined the trial, Rezvani says. But after treatment, the researcher notes, she “walked out of the ward to a pretty normal life.”   

Although some tumors resumed growing, of the 13 high-dose patients, seven were still in remission after 5 to 11 months. Without the treatment, many would have likely died in that period, Nieto says. Two were healthy enough to get a stem cell transplant, which can cure the disease. The team hopes that with repeated treatments with the antibody-coated NK cells—they plan to go up to four—the combination alone may be enough to shrink tumors for years.

Miller calls the work “a nice study” and says the approach could make it easier to stockpile NK cell treatments so they are ready for patients more quickly. But he adds that it’s hard to disentangle the effects of the antibody-treated cells from the direct infusions of AFM13 patients got later. He’s also cautious about whether the treatment will keep tumors in check over the long term.

source: sciencemag.org