CAR-T ‘robustly effective’ in younger patients with deadly form of brain cancer
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Younger patients with diffuse midline glioma experienced prolonged clinical improvement after receiving an investigational chimeric antigen receptor T-cell therapy, study results demonstrated.
Updated phase 1 trial data presented at American Association for Cancer Research Annual Meeting showed patients experienced periods of radiographic and clinical improvement after receiving multiple doses of the treatment. It is one of the first CAR T-cell therapies to show a durable benefit in multiple patients with solid tumors, according to the investigators.
Background
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, and Michelle Monje, MD, PhD, professor in the department of neurology at Stanford University and an investigator at Howard Hughes Medical Institute, led the trial.
Monje has been studying diffuse midline gliomas for more than two decades. It is among the most common forms of pediatric brain cancer and is “universally lethal, usually within a year,” she said.
“It is a horrific disease that we used to know very little about,” she told Healio.
Monje credited patients who donated their biopsy or autopsy specimens to help advance knowledge of the disease and make the new treatment possible. Using such tissue resources, ground-breaking clinical research done by Monje and colleagues at Stanford identified the treatment target used in their CAR T cells.
“[This is] an incredibly promising strategy and the only thing I’ve ever seen be robustly effective against this disease,” she said. “It truly feels as though we are finally taking steps in the right direction to treat this terrible disease, and I’m hopeful that this approach will ultimately be a very important part of an effective treatment for this horrible type of cancer.”
Methodology
Results from the study presented at last year’s AACR Annual Meeting showed the therapy caused radiographic tumor regressions but lacked durability, according to Robbie G. Majzner, MD, assistant professor of pediatrics in the division of hematology and oncology at Stanford University.
“We had one amazing response to this therapy, but it came back less than 90 days later,” he told Healio. “We realized that we needed to retreat patients more frequently.”
The investigators initially waited for disease progression to occur before providing additional doses to patients, Majzner explained. A year later, this strategy has shifted to additional doses at an average of 6 weeks apart (range, 4-8) via intracerebral ventricular administration directly into central nervous system fluid.
The trial also started treating patients at dose level 2, which tripled the initial IV dose to 3 million cells/kg.
“With this we have seen several patients have more durable radiographic and clinical responses,” Majzner said.
The novel CAR T-cell therapy the group at Stanford University developed targets the disialoganglioside GD2, a glycolipid found on the surface membrane of nerve cells and highly expressed in H3K27M-mutated gliomas. The cells are manufactured on-site using the closed-loop CliniMACS Prodigy (Miltenyi Biotec) system.
Majzner and colleagues enrolled 13 patients (median age, 14 years; range 4-30) in the single-center phase 1 dose-escalation study. Eleven patients received the investigational treatment, including eight patients at dose level 2.
Patients initially received IV doses of the therapy and are receiving subsequent doses via intracerebral ventricular administration due to its improved efficacy and safety, Majzner said.
Key findings
Three patients treated at dose level 2 experienced dose-limiting toxicity in the form of grade 4 cytokine release syndrome. All patients had symptoms resolved using standard care methods.
No dose-limiting toxicities occurred for patients treated at dose level 1.
Researchers observed earlier onset of CRS symptoms among patients treated at dose level 2 (median, 3 vs. 7 days).
No study patient developed high-grade CRS after intracerebroventricular administration of GD2-directed CAR-T.
All patients treated at either dose level experienced symptoms of tumor inflammation-associated neurotoxicity (TIAN) that resolved with anakinra (Kinaret, Sobi) or a combination of cerebrospinal fluid drainage and dexamethasone.
Intracerebroventricular administration has a superior safety profile because it resulted in limited proinflammatory cytokines in peripheral blood, according to Sneha Ramakrishna, MD, an instructor of pediatrics in the division of hematology and oncology at Stanford University who conducted the trial’s correlative analyses.
Results have shown local inflammation in the cerebrospinal fluid after intracerebroventricular administration as opposed to the systemic inflammation throughout the body when CAR-T is given intravenously.
“Patients were able to tolerate the [intracerebroventricular] dose administrations much better than IV dosing, while still gaining significant clinical benefit from each CAR T-cell administration,” she told Healio. “This is a critical learning point in our trial, and it has informed our thinking about next steps for this therapy.”
Of 10 patients available for follow-up evaluation of treatment efficacy, nine showed evidence of radiographic or clinical improvement of symptoms after IV infusion of GD2-directed CAR-T.
Four patients demonstrating clinical and radiographic benefits from therapy are still being treated with intracerebroventricular infusions as of the study cutoff date. Two patients have showed greater than 95% reduction in tumor volume resulting from treatment.
Clincial implications
Finding a scientific way to evaluate the success of this therapy is difficult because the volume of tumor regression doesn’t reflect the improvements in quality of life, Majzner told Healio. Things that don’t appear on a scan, such as being able to clasp a hand, regain the ability to walk or — as in the case of one patient he highlighted — watching a young girl with debilitating neurologic effects from her tumors zip across a sidewalk on a scooter after receiving the investigational therapy.
“The infiltrative nature of this disease makes radiographically assessing the response difficult,” Majzner told Healio. “We've integrated patient-reported outcomes into the trial to prospectively gather data about how our patients have improved from a personal perspective.”
Further study from this trial includes a newly opened dose-escalation arm using intracerebroventricular administration only, the results of which will be reported at future major meetings, Majzner said.
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