Can CAR-T cancer treatments be fine-tuned to avoid toxic side effects?

CAR-T treatments show promise in treating blood cancers like leukemia, but researchers are trying to lower the risk of side effects.

At the American Society of Hematology (ASH) meeting in San Diego, Kite Pharma and Novartis presented impressive data on their chimeric antigen receptor T-cell (CAR-T) therapies to treat blood cancers, and both appear to be on track to file for FDA approval soon. But concerns about toxic side effects continue to dog this emerging form of immunotherapy, particularly in the wake of Juno Therapeutics’ halted CAR-T trial, which has been plagued by patient deaths from neurological side effects.

Now a set of researchers at the Fred Hutchinson Cancer Research Center in Seattle who are partially funded by Juno are investigating methods for fine-tuning CAR-T treatments—and they presented early signs of success at ASH. On December 3, they announced positive results from an early trial of a highly targeted T-cell treatment in patients with chronic lymphocytic leukemia (CLL) who had exhausted all other treatment choices.

The CAR-T cells used by the Hutch scientists differ from those currently in large-scale clinical trials because they are engineered into two distinct subsets. As is the case with more advanced CAR-T therapies, they are made by extracting T cells from patients and then engineering them so they can recognize and kill cancer cells by targeting CD19, a molecule on the surface of blood cells implicated in CLL. But the Hutch therapy uses a one-to-one combination of the two different cell subsets that are selected.

Of the 19 patients in the trial who received the therapy along with chemo, 14 experienced a partial or complete regression of their disease, according to the Hutch. Those who had the most CAR-T cells in their blood after the treatment were most likely to have a complete response.

One patient did die from side effects, but for the other participants, toxic effects were temporary, according to the Hutch. And in a separate ASH presentation, the Hutch researchers announced that they have identified biomarkers that are linked to the development of severe toxicities after CAR-T treatments. They believe that by creating subsets of CAR-T cells for each patient, they’ll be able to choose dosages of cells that will both improve the benefits and reduce the risk of side effects.

Ever since CAR-T treatments emerged a few years ago, scientists all over the world have been looking for ways to reduce the risks associated with them—and some of those efforts have been bearing fruit recently. Another adverse effect of the treatments is that they deplete healthy B cells in the blood. In October, a group of scientists at Technical University München published a study in a mouse model of leukemia showing that an EGFR antibody could prevent CAR-T cells from going after healthy B cells.

And in June, researchers at the University of Pennsylvania, who have teamed up with Novartis to develop CAR-T therapies, showed in a mouse model that adding a cancer-associated carbohydrate to the cells could lower the potential for toxic side effects.

The Fred Hutch researchers hope their latest findings will lead to diagnostic tests that oncologists will be able to use to predict and mitigate the risk of toxic effects, said Cameron Turtle, a Hutch oncologist and one of the leaders of the trial. Although the trial presented at ASH was small, he expressed confidence that it showed the scientists are on the right track when it comes to improving CAR-T treatments. "It's very pleasing to see patients with refractory disease respond like this," he said.