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Engineered T cell therapy clears incurable childhood brain tumor in mice

April 18, 2018, New York — Engineered human immune cells can vanquish a deadly pediatric brain tumor in a mouse model, according to a study led by Michelle Monje and Crystal Mackall, both investigators at the Ludwig Center at Stanford University. The study, published online April 16 in Nature Medicine, represents the first time a severe brainstem cancer, diffuse intrinsic pontine glioma (DIPG), has been eradicated in a mouse model of the cancer. DIPG affects a few hundred school-age children across the country each year and has a median survival time of only 10 months; there is no cure.

In mice whose brainstems were implanted with human DIPG, engineered immune cells known as chimeric antigen receptor T cells—or CAR-T cells—were able to eliminate tumors. When the brains of the treated mice were examined by immunostaining, the animals had, on average, a few dozen cancer cells left, compared with tens of thousands of cancer cells in animals that received a control treatment. However, some mice experienced dangerous levels of brain swelling—a side effect of the immune response triggered by the engineered cells, suggesting that extreme caution will be needed in translating the approach into human clinical trials.

To begin the research, the scientists screened human DIPG tumor cultures for surface molecules, or antigens, that could serve as targets for CAR-T cells. In CAR-T therapies, the patient’s own immune cells are removed, engineered to attack an antigen on cancer cells, and reinfused into the patient. Monje’s team identified a sugar molecule, GD2, which is abundant on the surface of DIPG tumors in 80% of patients.

The researchers report that excess expression of the sugar is caused by the same mutation that drives the growth of most DIPG tumors, known as the H3K27M mutation. Scientists have known for decades that GD2 levels are high in some other forms of cancer, but its discovery on this tumor came as a surprise, says Mackall, whose laboratory had already designed CAR-T cells that attack the GD2 sugar.

DIPG tumors were undetectable after 14 days in mice that received GD2 CAR-T cells, while mice receiving the control treatment had no tumor regression. In the GD2 CAR-T treated animals, residual cancer cells did not express GD2, suggesting that these remaining cells were not vulnerable to the immune therapy and might cause a recurrence of the cancer.

Gliomas occurring in the spinal cord and thalamus of children also exhibit the H3K27M mutation and were also found to express very high levels of GD2. The research team found that spinal cord tumors in mice were also effectively cleared by the GD2 CAR-T cells. Some animals with thalamic tumors, however, died from the CAR-T treatment due to brain swelling, which is particularly risky near the thalamus.

The team plans to move the CAR-T treatment into human clinical trials, but will build as many safeguards as possible into the trial to minimize risks to people who participate. Because the CAR-T cells do not eradicate all cancer cells, the researchers think the immune therapy will need to be combined with other treatments.

A more detailed release from which this summary is derived can be found here.


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