2022 Top Story in Brain Cancer: GD2-CAR T-Cell Therapy for H3K27M-Mutated Diffuse Midline Gliomas

H3K27M-mutated diffuse midline gliomas (DMG), which include diffuse intrinsic pontine gliomas (DIPG), are rare tumors occurring in children and young adults that are universally lethal. Despite extensive research, there has been little progress in developing more effective therapies for these tumors. Standard treatment still consists of radiotherapy, and survival is usually less than 1 year.

In previous studies, Monje, Mackall, and colleagues had discovered that the disialoganglioside GD2 is highly expressed on H3K27M-mutant glioma cells. In preclinical studies they demonstrated promising efficacy of GD2-directed chimeric antigen receptor (CAR) T cells, providing the rationale for a first-in-human phase I clinical trial (NCT04196413).¹

In a paper recently published in Nature, ² they report on the results of the first 4 patients with H3K27M-mutant DIPG/DMG treated with GD2-CAR T cells at dose level 1 (1e6 GD2-CAR T cells/kg administered intravenously). While the initial infusion was administered intravenously, those patients who benefited from this treatment were eligible for subsequent GD2-CAR T infusions administered intraventricularly. Given the location of the DIPG in the brainstem, any inflammation resulting from the GD2-CAR T could result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts. To address this, patients were carefully monitored and neurocritical care precautions were incorporated.

Of the 4 patients enrolled, 3 had DIPG and 1 had spinal cord DMG, with ages ranging from 5 to 25 years.

Patient 1 was a 14-year-old female with H3K27M+ DIPG who presented with cranial nerve symptoms. On day +6 following GD2-CAR T, she experienced grade-1 cytokine release syndrome (CRS) with fever together with worsening cranial nerve symptoms consistent with tumor inflammation-associated neurotoxicity (TIAN) requiring treatment with tocilizumab (IL-6 antagonist) and corticosteroids. On day +9, she developed evidence of increased intracranial pressure that improved with draining of cerebrospinal fluid (CSF) from her Ommaya reservoir. She was treated with steroids and anakinra (IL-1 antagonist). MRI at 1 month showed progression, and she died at 3 months. Postmortem brain examination demonstrated substantial infiltration of lymphocytes in the tumor, which is uncharacteristic for DIPG. RNAscope identified cells expressing GD2-CAR mRNA transcript in the tumor, but not unaffected cortex. GD2-CAR transgene was detected by qPCR of DNA from tumor tissue. GD2-antigen expression was substantially higher in the tumor than in normal brain tissue. Tumor microglia/myeloid cell infiltration was prominent.

Patient 2 was a 21-year-old male with H3K27M+ DIPG who also developed CRS and TIAN 7 days post infusion of GD2-CAR T. Following treatment with tocilizumab and anakinra, he improved after 2 weeks. His clinical exam and imaging studies initially improved, but at 2 to 3 months his symptoms returned. He received a second dose of GD2 CAR T intraventricularly. He developed obstructive hydrocephalus requiring drainage of CSF from his Ommaya reservoir. His symptoms eventually improved, and he received three more infusions of GD2 CAR T. Unfortunately, 10 months after first receiving GD2 CAR T, he died from an intratumoral hemorrhage.

Patient 3 was a 5-year-old female with H3K27M+ DIPG. She also developed CRS and TIAN but improved significantly with time over subsequent weeks. She received an additional GD2 CAR T infusion but developed a mixed response, with improvement in some areas and progression in others, and eventually died 7 months after her first GD2 CAR T infusion.

Patient 4 was a 25-year-old female with H3K27M+ spinal cord DMG centered at thoracic levels T10–T12. After trial enrollment and before treatment, she progressed and no longer met eligibility criteria and was removed from the study. She did receive GD2 CAR T and exhibited a 90% reduction in tumor volume by day 47 and clinical improvement. Her brain metastasis, however, did not decrease in size. By day 75, both the spine and brain tumors progressed. A brain lesion was resected and showed robust GD2 expression but few infiltrating T cells. She received another GD2 CAR T infusion (50e6 GD2 CAR T cells) intraventricularly. She developed grade 4 immune effector cell–associated neurotoxicity requiring therapy and improved after several days. Her spinal cord tumor regressed by 80% and some of the intracranial lesions also improved. She progressed 2 months later and died 11 months after her first GD2 CAR T infusion.

These cases showed that GD2 CAR T therapy produced toxicities that were largely related to tumor location and reversible with intensive supportive care. On-target, off-tumor toxicity was not observed. Of the 4 patients, 3 exhibited clinical and radiographic improvement, although the responses were not very durable. Proinflammatory cytokines were increased in plasma and CSF. Transcriptomic analyses of 65,598 single cells from CAR T-cell products and CSF elucidate heterogeneity in response among patients and administration routes. Despite the toxicities and the variable results, these preliminary cases suggest that GD2 CAR T-cell therapy holds significant promise for H3K27M+ DIPG/DMG, and additional results from this trial are eagerly awaited.