An immune-cell therapy shrank children's brain tumors, restored neurologic function and - for one participant in a Stanford Medicine clinical trial - erased all detectable traces of a brain cancer typically considered incurable.
The trial, among the first successes against solid tumors for engineered immune cells known as CAR-T cells, offers hope for children with a group of deadly brain and spinal cord tumors, including a cancer called diffuse intrinsic pontine glioma, or DIPG. The findings will be published online Nov. 13 in Nature. In October, this therapy received a regenerative medicine advanced therapy designation from the U.S. Food and Drug Administration, which gives the researchers access to a fast-tracked version of the FDA approval process.
Of the 11 participants who received CAR-T cells in the trial, nine showed benefits. Nine had functional improvement in the disabilities caused by their disease. Four 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 the trial's lead author, Michelle Monje , MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology and 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.
Drew was diagnosed with DIPG in November of 2020, during his junior year of high school. He'd gone to the doctor because of unusual headaches, odd movements of his left eye and partial paralysis on the left side of his face. As the tumor grew, it affected his hearing, balance and gait. He needed a wheelchair to move all but short distances.
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, and no effective chemotherapy drugs exist. Because their malignant cells intermingle with healthy cells in key neurologic structures, the tumors cannot be surgically removed. DIPG, the subtype of disease that occurs in the brainstem, has a five-year survival rate below 1%.
Against this bleak landscape, the research team was not sure how much to expect from the CAR-T cells, even though preclinical studies in rodents had been promising. CAR-T cells, or chimeric antigen receptor T cells, are made by removing some of a patient's own T cells and modifying them to bind to a specific molecular target. The cells are returned to the patient's body, where they trigger an immune response against cancer cells that have the molecular target. CAR-T cells have been approved by the Food and Drug Administration 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 the study's senior author, Crystal Mackall , MD, the Ernest and Amelia Gallo Family Professor and professor of pediatrics and of medicine.
As the tumors progress, they cause profound disability. Patients may lose their ability to walk, smile, swallow, hear and talk. They may experience neuropathic pain resulting from spinal cord damage, often a severe shooting or burning pain, as well as paralysis, loss of sensation and incontinence.
Before the trial, the researchers weren't sure if shrinking the tumors could address the terrible symptoms, Mackall said. But afterward, "We could see clear evidence of reversibility."
Finding the right target
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 a surface marker called GD2. Mackall's team had already engineered CAR-T cells to target GD2, which is found on a few 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.
After intravenous dosing of cells, all participants had some degree of cytokine release syndrome, aka "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.
In the four people with the best responses, tumor volumes shrank by 52%, 54%, 91% and 100%.
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.
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. The scientists are also studying how to take advantage of the tumors' biological quirks with targeted therapies.
"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."
A teary graduation
After Drew was diagnosed with DIPG, his neuro-oncologist at a children's hospital in the Midwest recommended the clinical trial at Stanford Medicine. In June of 2021, he received his first infusion of CAR-T cells, into his bloodstream; it caused vomiting, shivering and temporary worsening of neurological symptoms such as poor balance.
It was challenging, Drew said, "but the MRIs proved that it worked well, so the CAR-T cells did their job."
"I would describe it to somebody like cleaning out your garage," said Drew's mom. "When you clean out your garage, it looks worse before it gets better."
Drew's second CAR-T infusion - the first time he received cells directly into his cerebrospinal fluid - also caused some side effects. But with subsequent infusions of cells, the side effects diminished.
He underwent the first two infusions during the summer between his junior and senior years of high school. His parents said he could take time off from school, his mom recalled, but Drew was determined to graduate with his class.
"He said 'No, I like to learn, and I just want to be like all my friends,'" she said.
Even as the trial continued, Drew didn't shy away from academic challenges, taking Advanced Placement classes in chemistry and calculus during his senior year. That fall, he did most of his classwork from home. But by the spring of 2022, as the CAR-T cells continued to attack the cancer cells and his tumor shrank more, he was back at school most of the time. His balance and walking improved, enabling him to navigate the hallways at school with a rolling walker.
When Drew graduated from high school in May of 2022 - on time, with his class - his tumor was gone. Nineteen months after he was diagnosed and eight months past the median survival time for DIPG, he walked across the stage at graduation unassisted.
He'd never sought the spotlight, but everyone at the ceremony knew the significance of the day. His parents cried tears of joy. One of their friends texted Drew's dad: "Thank goodness I brought tissues!"
His classmates gave him a standing ovation.
Focusing on a career
Drew continues to receive infusions of CAR-T cells every few months. Because he's the first person to experience a complete response to the cells, his medical team can't make any promises about what comes next. But everyone is hopeful he's cured.
He's now in his junior year of college, majoring in forestry with a chemistry minor. Although he still has left-sided facial paralysis, he can walk and run again, and his hearing and sense of taste
have improved. He enjoys living on his own and is focused not on cancer but on the usual hurdles of higher education.
The entire family - which includes Drew's two younger sisters - is grateful for the research that led up to the trial, especially that it was enabled by dozens of families who donated tumor tissue after losing their children to the same disease.
"There's a lot of loss that led to this research," Drew's dad said. "I hope those families know that this success is because of them."
Meanwhile, the research team continues to analyze hundreds of biological samples they collected in the trial. They are determining what distinguished the participants with the best responses.
"We've already gleaned some hypotheses about how to improve outcomes, both for this therapy and more broadly for immunotherapy for cancers in the central nervous system," Monje said. "There are really important lessons from this trial for brain tumor immunotherapy overall."
The findings have also been used to refine protocols for the CAR-T cell clinical trial. The researchers continue to enroll participants for the study . The FDA's regenerative medicine advanced therapy designation, which is intended to speed approvals of regenerative medicine treatments that show potential for treating life-threatening diagnoses, will give the scientists expedited access to regulatory experts to help refine and improve the research, with the hope of obtaining approval for the cell therapy.
"While this trial represents progress, we still have work to do to diminish the toxicity of treatment and enhance benefit for patients," Mackall added. "But now we have a path forward."
Drew has a path forward, too. After he graduates from college, he hopes to apply his degree to conservation work and restoration of natural areas after logging or other human use, also known as rewilding.
"Rewilding has really inspired me, and I think this is what I want to do," Drew said.
A researcher from Johns Hopkins School of Medicine contributed to the study. Mackall holds an appointment with the Parker Institute for Cancer Immunotherapy in San Francisco.
The research was funded by the Parker Institute for Cancer Immunotherapy, CureSearch, the National Cancer Institute (grants R01CA263500 and K08CA267057), the California Institute for Regenerative Medicine (grant CLIN2-12595), St. Baldrick's Foundation to the Empowering Pediatric Immunotherapy Immunotherapies for Pediatric Cancer Team, Alex's Lemonade Stand Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, ChadTough Defeat DIPG Foundation, and Oscar's Kids Foundation.
