CAR-T ‘effective’ in younger patients with deadly form of brain cancer

April 20, 2022

4 minute read


Source: Majzner RG, et al. Abstract CT001. Presented at the annual meeting of the American Association for Cancer Research; April 8-13, 2022; New Orleans.


Disclosures: Majzner reports consulting roles with Aptorum Group, Arovella, Illumina Radiopharmaceuticals, Link Cell Therapies, Lyell Immunopharma and NKARTA, and is co-founder and shareholder of Syncopation Life Sciences. He also holds several patents for CAR T-cell therapy, including a patent for GD2-directed CAR T cells for H3K27M diffuse midline gliomas with Monje and Mackall. Monje reports a consulting role at Cygnal Therapeutics. Ramakrishna does not report any relevant financial information. Please see the summary for all relevant financial disclosures from other researchers.


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Younger patients with diffuse midline glioma experienced prolonged clinical improvement after receiving experimental chimeric antigen receptor T-cell therapy, study results demonstrated.

Updated phase 1 trial data presented at the annual meeting of the American Association for Cancer Research showed that patients experienced periods of radiographic and clinical improvement after receiving multiple doses of the treatment. According to the researchers, it is one of the first CAR T-cell therapies to show lasting benefit in several patients with solid tumors.


Quote from Michelle Monje, MD, PhD.



Background

Crystal L. Mackall, MD, Ernest and Amelia Gallo Professor of Pediatrics and Family Medicine at Stanford University School of Medicine and Founding Director of the Stanford Center for Cancer Cell Therapy, and Michelle monjeMD, PhD, professor in the department of neurology at Stanford University and researcher at the Howard Hughes Medical Institute, led the trial.

Monje has studied diffuse midline gliomas for more than two decades. It is among the most common forms of childhood brain cancer and is “universally fatal, usually within a year,” she said.

“It’s a horrible disease that we knew very little about,” she told Healio.

Monje thanked the patients who donated their biopsy or autopsy samples to help advance knowledge about the disease and make the new treatment possible. Using these tissue resources, groundbreaking clinical research led by Monje and colleagues at Stanford has identified the processing target used in their CAR T cells.

“[This is] an incredibly promising strategy and the only thing I have ever seen to be effective against this disease,” she said. “I really feel like we are finally taking steps in the right direction to treat this terrible disease, and I hope this approach will ultimately be a very important part of an effective treatment for this horrible type of cancer.

Methodology

Study results 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 an amazing response to this therapy, but it came back less than 90 days later,” he told Healio. “We realized we needed to remove patients more frequently.”

Researchers first waited until the disease progressed before providing additional doses to patients, Majzner explained. A year later, this strategy transitioned to additional doses at an average of 6 week intervals (range, 4-8) via intracerebral ventricular delivery directly into central nervous system fluid.

The trial also began treating patients at dose level 2, which tripled the initial IV dose to 3 million cells/kg.

“With this, we’ve seen multiple patients have longer-lasting radiographic and clinical responses,” Majzner said.

The new CAR T-cell therapy developed by the Stanford University group targets disialoganglioside GD2, a glycolipid found on the surface of nerve cell membranes and highly expressed in H3K27M– mutated gliomas. The cells are fabricated on site using the CliniMACS Prodigy closed-loop system (Miltenyi Biotec).

Majzner and colleagues enrolled 13 patients (median age, 14 years; range 4 to 30 years) in the phase 1, single-center, 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 by intracerebral ventricular delivery due to its improved efficacy and safety, Majzner said.

Main conclusions

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 methods of care.

No dose-limiting toxicity occurred in patients treated at dose level 1.

Researchers observed an earlier onset of CRS symptoms in patients treated at dose level 2 (median, 3 versus 7 days).

No patient in the study developed high-grade CRS after intracerebroventricular administration of GD2-directed CAR-T.

All patients treated at either dose experienced symptoms of tumor inflammation-associated neurotoxicity (TIAN) that resolved with anakinra (Kinaret, Sobi) or combination cerebrospinal fluid drainage -spinal and dexamethasone.

According to Sneha Ramakrishna, MD, a pediatric instructor in the division of hematology and oncology at Stanford University who conducted the correlative analyzes of the trial.

The results showed local inflammation in the cerebrospinal fluid after intracerebroventricular administration as opposed to systemic inflammation throughout the body when CAR-T is administered intravenously.

“Patients were able to tolerate [intracerebroventricular] dose administrations are much better than IV doses, while still enjoying significant clinical benefit from each administration of CAR T-cell,” she told Healio. “This is a critical learning point in our trial, and it has informed our thinking about the next steps in this therapy.”

Of 10 patients available for follow-up evaluation of treatment efficacy, nine showed signs of radiographic or clinical improvement in symptoms after GD2-directed IV infusion of CAR-T.

Four patients demonstrating clinical and radiographic benefit of the therapy are still being treated with intracerebroventricular infusions at the study end date. Two patients showed greater than 95% reduction in tumor volume as a result of the treatment.

Clinical implications

Finding a scientific way to assess the success of this therapy is difficult because the volume of tumor regression does not reflect improvements in quality of life, Majzner told Healio. Things that don’t show up on a CT scan, like being able to shake a hand, regaining the ability to walk, or – as in the case of one patient he pointed out – looking at a young girl with debilitating neurological effects of his tumors cross a sidewalk on a scooter after receiving the experimental therapy.

Majzner_Robbie_80x106

Robbie G. Majzner

“The infiltrative nature of this disease makes radiographic assessment of response difficult,” Majzner told Healio. “We incorporated patient-reported outcomes into the trial to prospectively gather data about our patients’ improvement from a personal perspective.”

Further study of this trial includes a newly opened dose escalation arm using only intracerebroventricular delivery, the results of which will be reported at future major meetings, Majzner said.

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