New Strategy for Preventing Relapse After CAR T-Cell Therapy

Scientists have developed a booster treatment that could improve the efficiency of existing CAR T-cell therapies for cancer by addressing their major shortcoming: a high rate of relapse, even in patients whose cancer goes into full remission.

The team created the CAR-Enhancer (CAR-E) therapeutic platform to spur CAR T cells to be more active and persist longer in the body, enabling them to remain in battle mode until all tumor cells are eliminated.

The platform also prompts CAR T cells to form a memory of the cancer cells so they can spring back into action if the cancer recurs.

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In experiments in animal models and human-derived cancer cell lines, the researchers found that CAR-E worked together with CAR T cells to eradicate all tumor cells. The next step is to test the platform in human clinical trials.

The research, led by scientists at Harvard Medical School and Dana-Farber Cancer Institute, was published July 30 in Nature Biotechnology.

Addressing a CAR T relapse roadblock

CAR T cells are genetically enhanced versions of a patient’s own cancer-fighting T cells. They’re made by removing a few million T cells from a patient’s blood and genetically equipping the T cells to produce a tumor-fighting surface structure called a chimeric antigen receptor, or CAR. The CAR is designed to latch onto a specific marker, or antigen, on the patient’s tumor cells.

The altered T cells — now CAR T cells — are expanded in the lab until they number in the hundreds of millions. When they are infused back into the patient, their specially designed receptor locks onto the tumor cell antigen and triggers an immune attack on the cancer.

CAR T-cell therapies have revolutionized the treatment of certain blood cancers, including B-cell leukemias and lymphomas and multiple myeloma. However, patients have a high rate of relapse. Researchers report that this is because the CAR T cells leave a small number of tumor cells behind.

“The attack destroys nearly all the tumor cells, but a tiny percentage remains,” said senior author Mohammad Rashidian, HMS assistant professor of radiology at Dana-Farber. He added that CAR T cells stop working once they can’t find any more cancer cells to kill, setting the stage for the remaining tumor cells to cause the cancer to return.

Rashidian estimates that virtually 100 percent of patients with myeloma initially respond to CAR T-cell therapies, but almost all eventually relapse — with half relapsing within one to two years. In general, patients relapse as CAR T cells in their bloodstream disappear.

Rashidian noted that most research to address the high rate of relapse has focused on reengineering the CAR T cells themselves — for example, by adding or removing genes to keep the cells active longer.

“While these approaches hold great promise, they have yet to show much effectiveness in the clinic. We decided to come at the problem from a completely different perspective,” he said.

Supercharging CAR T cells

Rashidian and his team developed the CAR-E platform to enhance CAR T cells from the outside.

The platform delivers a fused molecule consisting of a weakened form of the immune signaling protein interleukin-2 (IL-2) and the antigen the CAR is designed to bind to. In tests, the platform extended CAR T cells’ lives and prompted them to form memory.

The weakened form of IL-2 still has a strong effect on T cells, Rashidian said, but is less toxic — and it leaves normal T cells alone while stimulating the CAR T cells it’s targeted to.

The targeting is accomplished by fusing IL-2 to B-cell maturation antigen (BCMA), which binds to multiple myeloma CAR T-cell therapies.

“Just like weak IL-2, the BCMA antigen by itself doesn’t affect CAR T cells, but together, they have a synergy whose impact was well beyond our expectations,” said lead author Taha Rakhshandehroo, a postdoctoral researcher at Dana-Farber.

In animal models and in laboratory cultures of human myeloma cells, CAR-E caused CAR T cells to both proliferate and diversify, generating different types of CAR T cells with different properties.

“It generated a complete repertoire of the kinds of T cells needed for an effective immune response to cancer,” Rashidian said.

CAR-E therapy also completely cleared tumor cells, erasing any sign of the cancer.

What comes next

The long-lasting CAR T cells generated by the therapy could be restimulated by readministering CAR-E, the authors said. This suggests that patients who relapse after CAR T-cell therapy could be treated with additional doses of CAR-E.

The study also raises the possibility that CAR-E could allow patients to be treated with fewer CAR T cells, which would save time and money and reduce side effects such as cytokine release syndrome.

First, however, future clinical trials would need to ensure that CAR-E is safe and effective in humans. The trials would also need to determine the best dose and schedule of administration.

The researchers expect that CAR-E treatment would begin about a month after patients were infused with CAR T cells and would consist of a weekly dose for three or four weeks.

“The most exciting part of this therapy is how easily it can be integrated into the care of patients receiving CAR T-cell therapies,” Rakhshandehroo said. “It’s such an elegant solution to the problem of CAR T-cell depletion. We’re eager to begin testing it in clinical trials.”

Adapted from a Dana-Farber press release.