Clinical trial results are showing the first successes against solid tumors for CAR-T cells. The findings offer hope for children with a group of deadly brain and spinal cord tumors, including a cancer called diffuse intrinsic pontine glioma, or DIPG. The immune-cell therapy shrank children’s brain tumors, restored neurologic function and—for one participant—erased all detectable traces of a brain cancer typically considered incurable.
The findings are published in Nature in the paper, “Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas.”
Of the 11 participants who received CAR-T cells in the trial, nine showed benefits and had functional improvement in the disabilities caused by their disease. Four participants had the volume of their tumors reduced by more than half and one of those four participants had a complete response (meaning his tumor disappeared from brain scans). Although it is too soon to say whether he is cured, he is healthy four years after diagnosis.
“This is a universally lethal disease for which we’ve found a therapy that can cause meaningful tumor regressions and clinical improvements,” said Michelle Monje, MD, PhD, professor of neurology at Stanford Medicine. “While there is still a long way to go to figure out how to optimize this for every patient, it’s very exciting that one patient had a complete response. I’m hopeful he has been cured.” The patient, 20-year-old Drew, wants his outcome to be the first of many. “I’m hoping they’ll learn from all my successes to help other kids,” he said.
Diffuse midline gliomas, which can grow in the brain or spinal cord, are diagnosed in a few hundred children and young adults in the United States annually and have a median survival time of about a year. Radiation therapy offers only temporary relief, no effective chemotherapy drugs exist, and the tumors cannot be surgically removed. DIPG, the subtype of disease that occurs in the brainstem, has a five-year survival rate below 1%.
CAR-T cells have been approved by the FDA since 2017 to treat blood cancers but have not been as successful against solid tumors. In the new study, “one of the biggest surprises was how much clinical benefit we saw,” said Crystal Mackall, MD, the Ernest and Amelia Gallo Family Professor and professor of pediatrics and of medicine.
The type of CAR-T cell therapy used in the trial was developed at Stanford Medicine: In 2018, Monje’s team discovered that DIPG and other diffuse midline glioma tumor cells produce a large amount of the surface marker GD2. Mackall’s team had already engineered CAR-T cells to target GD2, which is found in other cancers. The researchers showed that GD2-targeting CAR-T cells eradicated DIPG tumors in animal models.
The new study reports on the first 13 patients enrolled in the ongoing trial, which is open to those who have DIPG or spinal cord diffuse midline glioma. Participants’ median age was 15 years, and their tumors were diagnosed a median of five months before they joined the trial. Ten had DIPG, and three had spinal cord diffuse midline glioma. (Two participants’ tumors progressed so rapidly that they became ineligible for the study before receiving CAR-T cells.)
Because this was the first human trial of CAR-T cells for DIPG, the researchers primarily wanted to establish that they could manufacture cells for each person, identify a safe dose of the cells, and monitor side effects. Their secondary aim was to start assessing clinical benefits.
Before receiving the CAR-T cells, participants had chemotherapy to prevent their immune systems from attacking the engineered cells. They received the first dose of CAR-T cells intravenously, and the researchers monitored them for immune and neurological side effects.
Specifically, Arm A of the Phase I trial no. NCT04196413 “administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg−1; DL2, 3 × 106 kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106 GD2-CART).”
After intravenous dosing of cells, all participants had some degree of cytokine release syndrome (cytokine storm) with symptoms such as fever and low blood pressure, as well as temporary neurological side effects due to inflammation within the tumor. The team tested two doses of CAR-T cells and determined that the lower dose was safer because it led to less severe cytokine storm side effects.
Of the 11 participants receiving CAR-T cells, nine experienced benefits: a reduction in their tumor volume, an improvement in function on a neurologic exam, or both. These nine participants received additional doses of CAR-T cells infused into the cerebrospinal fluid in their brains.
Infusing the cells directly into the cerebrospinal fluid caused fewer side effects. Participants continued receiving cell infusions into the brain every one to three months as long as it benefited them. In general, participants experienced less inflammation with later cell infusions. The researchers said that in subsequent arms of the trial, they will test infusing cells into the cerebrospinal fluid from the start.
Most of the nine participants who benefited from CAR-T cells experienced improvement in neurologic symptoms and reductions in tumor size. However, two had reduced symptoms without change in overall tumor volume. As their tumors shrank, several participants regained abilities they had lost, such as walking, or experienced reversal of symptoms such as incontinence, paralysis, or neuropathic pain.
Study participants lived a median of 20.6 months after diagnosis, with two living longer than 30 months, and one, Drew, still alive four years after his DIPG diagnosis.
In the four people with the best responses, tumor volumes shrank by 52%, 54%, 91%, and 100%. The researchers analyzed the maximum decrease in all participants’ tumor sizes and found that the responses fit a normal distribution or bell curve, suggesting that Drew’s excellent response is not a fluke and that future patients can experience similar benefits. The research team is now investigating how they can improve on the therapy—for instance by suppressing aspects of the immune response to CAR-T cells that might favor the tumor.
“Sometimes this tumor grows so fast that it feels like a race between the CAR-T cells fighting and the cancer cells replicating,” Monje said. “A therapy that slows the growth of the tumor is going to help the CAR-T cells work better.”
In October, this therapy received a regenerative medicine advanced therapy designation from the FDA, which gives the researchers access to a fast-tracked version of the FDA approval process.
