CAR T-cell therapy produces ‘jaw dropping’ results for deadly pediatric brain tumors
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Key takeaways:
- CAR-T shrank tumors among certain young patients with deadly brain cancer.
- One patient achieved complete response and remains cancer free 4 years after diagnosis.
Chimeric antigen receptor T-cell therapy can reduce tumor burden and improve neurologic function for patients with certain brain and spinal cord cancers, a first-in-human clinical trial showed.
One young man — diagnosed at age 16 years with diffuse intrinsic pontine glioma — achieved complete response and remains healthy 4 years later.
“Frankly, our results were jaw dropping,” Crystal L. Mackall, MD, Ernest and Amelia Gallo family professor of pediatrics and medicine at Stanford University School of Medicine and founding director of Stanford Center for Cancer Cell Therapy, told Healio. “We, like many others, have seen CAR T cells have remarkable activity in liquid tumors but minimal effect in solid cancers. Here, we saw patients whose tumors were shrinking remarkably but, even more exciting, their clinical condition was improving. The results were well beyond my expectations.”
Children with this universally lethal cancer often “get neurologically more and more devastated” during the normal course of the disease, added Michelle Monje, MD, PhD, Milan Gambhir professor of pediatric neuro-Oncology at Stanford.
“Seeing them improve — and improve even to normal function — rapidly fills me with hope,” Monje told Healio. “I think we’re very clearly now on the right path.”
Background and methods
Prognosis is poor for individuals with H3K27M-mutated diffuse midline gliomas (DMGs).
Children and young adults who develop diffuse intrinsic pontine glioma (DIPG) survive a median 11 months, and only 1% live 5 years. Those with DMGs not in the brainstem survive a median 13 months, according to study background.
“It’s among the most difficult of all cancers to treat,” Mackall said. “This is the single-largest killer of children due to brain tumors in developed countries.”“
“Part of why they’re so difficult to treat [is because] we can’t surgically resect them,” Monje added. “It’s not a mass within the brainstem. It becomes part of the brainstem. Imagine it like glitter and Jell-O.”
Mackall described her research with Monje as “serendipity.”
Monje and colleagues had discovered DMG cells expressed the disialoganglioside GD2, and Mackall had already started work on making a CAR-T for that target.
As Healio previously reported, research published last year in The New England Journal of Medicine showed a CAR-T targeting GD2 produced anti-tumor responses among 63% of younger patients with relapsed or refractory high-risk neuroblastoma. Findings of the phase 1/phase 2 trial reflected some of the most promising results for CAR-T in solid tumors.
“It was one of the most rapid discovery-to-therapeutic testing that I can [recall],” Mackall said.
In the most recent trial, Mackall, Monje and colleagues enrolled 13 patients (median age, 15 years; range, 4-30; 53.8% women; 76.9% with DIPG) between June 2020 and Dec. 1, 2023.
Two individuals did not receive treatment on trial because of rapid cancer progression.
The other 11 participants had a median time from diagnosis to enrollment of 5 months (range, 3.9-11.6).
They received CAR-T at one of two doses — 1 x 10 kg (dose level 1; n = 3) or 3 x 10 kg (dose level 2; n = 8) — after lymphodepleting chemotherapy.
Patients who achieved clinical benefit and stable disease following their original dose could receive intracerebroventricular (ICV) infusions (10 to 30 x 10 GD2-CAR-T). They could receive additional ICV doses if they had continued benefit.
Feasibility of manufacturing and safety of dosage served as primary endpoints. Clinical improvement served as the secondary endpoint.
Results and next steps
Researchers produced 20 GD2-CAR-T products, with median manufacturing time of 7 days and median 22.9 days (range, 15-38) between enrollment and infusion.
No patients who received dose level 1 experienced dose-limiting toxicities. Three patients who received dose level 2 developed grade 4 cytokine release syndrome.
Every participant developed CRS.
Researchers determined dose level 1 to be the maximum tolerated dose.
Nine patients had a clinical benefit and received ICV, and several those received additional infusions.
Four had their tumors decrease by at least 50% (52%, 54%, 91%, 100%). Three others had smaller tumor reductions.
Researchers reported median OS of 20.6 months, with two patients surviving longer than 30 months.
The adolescent who achieved a complete response went from needing a wheelchair to hiking and jogging. He also had improved hearing and facial, body and taste sensation.
“This is a disease I’ve studied for the better part of 2 decades,” Monje said. “I had hoped that at some point in my career, I would see a patient get better. Having [seen a] complete response — now durable for 4 years — [and] getting to watch this patient grow up from a teenager to a young man, it fills me with hope, and it makes me believe that this is a curable disease.”
Other patients derived significant clinical benefits, too.
One 5-year-old girl did not have overall tumor reduction, but she regained the use of the right side of her body, including her hand, arm and leg.
“One of the most exciting things about this trial was that it wasn’t just about changes on an MRI — which is gratifying if you’re a neuro-oncologist — but it was that we saw clinical benefit, and we did not know that was even possible,” Mackall said. “We didn’t know if the deficits were permanent in these kids.”
The FDA granted regenerative medicine advanced therapy designation to this approach in October. Researchers continue to enroll patients into the trial and are investigating whether ICV alone is effective.
Mackall and colleagues plan to further evaluate why certain patients derived benefit and others did not, how the treatment impacts quality of life, and the importance of lymphodepletion. They also intend to evaluate combination strategies.
The clinical improvements observed demonstrate that although the disease infiltrates neural structures, it doesn’t destroy them, Monje said.
“That means that with effective therapy, people can regain function,” Monje said. “[That] is just an incredibly hopeful thing and really presents some urgency in figuring out how to optimize this quickly.”
References:
- Cell therapy fights lethal childhood brain cancer in Stanford Medicine trial (press release). Available at: https://med.stanford.edu/news/all-news/2024/11/car-t-brain-cancer.html. Published Nov. 13, 2024. Accessed Nov. 13, 2024.
- Monje M, et al. Nature. 2024;doi:10.1038/s41586-024-08171-9.
For more information:
Crystal L. Mackall, MD, can be reached at cmackall@stanford.edu.
Michelle Monje, MD, PhD, can be reached at mmonje@stanford.edu.
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Monje M, et al. Nature. 2024;doi:10.1038/s41586-024-08171-9.
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