Novel CAR-T shows ‘promising early signs of clinical efficacy’ for diffuse midline gliomas
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Three of four patients who received an investigational chimeric antigen receptor T-cell therapy for diffuse midline glioma showed tumor regression and improvement in neurologic symptoms, according to early results of a phase 1 study.
The research — presented during the virtual American Association for Cancer Research Annual Meeting — also identified a previously undescribed yet manageable adverse effect of CAR T-cell therapy that may be specific to the targeting of central nervous system solid tumors, according to the researchers.
The novel CAR T-cell therapy — manufactured at Stanford University using the closed-loop CliniMACS Prodigy (Miltenyi Biotec) system — targets the disialoganglioside GD2, a glycolipid found on the surface membrane of nerve cells and highly expressed in H3K27M-mutated gliomas.
GD2-directed therapy for CNS tumors has shown the ability to navigate a narrow therapeutic window and provide antitumor activity without damaging other parts of the brain, according to Robbie G. Majzner, MD, assistant professor of pediatrics in the division of hematology and oncology at Stanford University.
“Average life expectancy for a patient that is diagnosed with [diffuse intrinsic pontine glioma] is less than 1 year,” he said during a presentation.
Majzner and colleagues published the first preclinical evidence of the effectiveness of GD2-directed CAR T cells for diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas. Despite tumor remissions in most of their preclinical models, these experiments showed evidence of increased inflammation during peak CAR T-cell activity, which could translate to treatment-related adverse events when tested in humans.
“With this in mind, we designed a phase 1 trial to assess the feasibility and safety of GD2-CAR T cells for diffuse midline gliomas,” he said.
The researchers presented data on the first four patients (75% female, age range, 4-25 years) in the dose-escalation study who received the GD2-CAR T-cell therapy for H3K27M-mutant DIPG (n = 3) and spinal cord diffuse midline glioma (n = 1).
The patients with DIPG received the initial cell IV dose of 1 × 106 GD2-CAR T cells/kg. The patient with spinal cord diffuse midline glioma had to be withdrawn from the study after experiencing rapidly progressive disease, but received the investigational CAR-T at the initial dose after researchers obtained an emergency investigational new drug application waiver from the FDA.
All study patients had an Ommaya reservoir implanted to monitor intracranial pressure. They also underwent lymphodepletion with cyclophosphamide and fludarabine before infusion with CAR T cells.
Results showed all four patients experienced cytokine release syndrome, with one case of grade 3 CRS. Two patients also experienced grade 1 to grade 2 immune effector cell associated neurotoxicity syndrome.
Patients received conservative fluid resuscitation and other standard interventions to prevent an increase in intracranial pressure after CAR-T infusion.
Researchers observed no evidence of on-target, off-tumor toxicity in any patient, Majzner said. However, he described a newly described toxicity associated with the therapy that researchers believe may be specific to the use of CAR T cells for CNS tumors.
The toxicity, which Majzner called tumor inflammation-associated neurotoxicity (TIAN), involves on-tumor inflammation that results from the activation or engagement of endogenous or infused T cells and/or other immune effector cells in the body. Symptoms of TIAN include worsening of baseline neurologic defects and, in severe cases, life-threatening hydrocephalus and potential cerebral herniation.
“TIAN is an important axis of inflammation in patients with brain tumors who receive CAR T-cell therapy and there will be a need for a consensus grading system,” Majzner said.
One patient in the study developed increased intracranial pressure due to TIAN that was resolved by removal of cerebrospinal fluid using the Ommaya reservoir, according to the researchers.
Analysis of clinical activity showed evidence of CAR T cells in the central nervous system, with detection of these cells in both peripheral blood and cerebrospinal fluid.
Three of four patients showed substantial improvement in neurological deficits or had evidence of radiographic improvement, including the patient treated on the emergency waiver, who 2 months after infusion demonstrated a more than 90% reduction in tumor volume.
Although it remains too early to assess the durability of the therapy, the results show “promising early signs of clinical efficacy,” Majzner said.
“GD2-CAR T cells are safe and have manageable toxicities that require very close monitoring and inpatient observation, as well as regular monitoring of [intracranial pressure],” he added.
Perspective
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Leo David Wang, MD, PhD
H3K27M-mutated diffuse midline gliomas are uniformly fatal, and there is a tremendous need for better therapies for these terrible diseases. Immunotherapy — and, in particular, adoptive cellular therapy — holds great promise for improving outcomes for these children.
Considering this, Majzner and colleagues’ reporting of these preliminary clinical trial results is extraordinarily exciting. There are a handful of groups conducting CAR-T trials for pediatric brainstem gliomas, but this one is special for a variety of reasons. First, the GD2-targeting CAR is novel. Second, adding lymphodepleting chemotherapy is something the field has been moving toward, but which the Stanford group was able to implement first. Third, the team behind this trial is truly outstanding. They have implemented a very well-designed trial that will capture rich data to help improve future studies.
The most exciting thing about this report may be the remarkable clinical improvement that patients experienced. Any gain in mobility or function, even if transient, is tremendously encouraging.
These findings highlight the enormous potential of adoptive cellular therapies for these diseases. They also underscore the importance of excellent and attentive supportive care; the physicians involved have done a phenomenal job safeguarding the health of their brave patients as they encounter new toxicities like TIAN.
Antigen heterogeneity and antigen escape remain significant challenges for CAR T-cell therapy, and it is likely that combinatorial approaches will be required for successful control of pediatric brain tumors. Approaches to entrain the endogenous immune response are particularly appealing and an area of active investigation. This study, and others like it, will permit researchers to identify additional therapeutic strategies to optimize CAR T-cell treatment.
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Majzner RG, et al. Abstract CT031. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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