Phase I trial of novel CAR-T cell therapy for pediatric midline gliomas

1. Approximately 88% of patients with GD2-positive diffuse midline glioma or other progressive CNS tumours receiving C7R-GD2.CARTs had a partial response to therapy or stable disease.

2. No dose-limiting toxicities were observed in any patient treated with GD2.CARTs or C7R-GD2.CARTs.

Evidence Rating Level: 2 (Good)

Study Rundown: Current treatment options remain limited for children with diffuse midline glioma (DMG), resulting in a poor prognosis for these patients. One promising novel approach is adoptive cell transfer involving T cells armed with chimeric antigen receptors (CART). While the efficacy of CART in CNS tumours has been traditionally limited by an immunosuppressive tumour microenvironment, this study sought to investigate whether a constitutively active IL-7R (C7R) could increase the antitumour response of CART.   In this phase I trial, pediatric patients with GD2-positive DMG and other CNS tumours were selected to receive CART directed against GD2 (GD2.CARTs) in a dose-escalating manner with 3 treatment cohorts. No dose-limiting toxicities were observed in any patients. 88% of patients receiving GD2.CARTs with constitutively active IL-7R (C7R-GD2.CARTs) experienced tumour inflammation-associated neurotoxicity (TIAN) while 75% of patients in the same subcohort experienced cytokine release syndrome (CRS). All adverse effects were resolved with anti-cytokine management involving tocilizumab or anakinra. Roughly 88% of patients receiving C7R-GD2.CARTs demonstrated partial response or stable disease following treatment. Overall, this study found that GD2.CARTs with and without C7R were well tolerated, with C7R-GD2.CARTs showing preliminary efficacy in the treatment of GD2-positive DMG. As such, treatment with C7R-GD2.CARTs may be a promising new therapeutic modality for pediatric patients with DMG and other CNS tumours with poor prognoses and therefore warrants further investigation.

Click to read the study in Journal of Clinical Oncology

Relevant Reading: Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results

In-Depth [Phase 1 Clinical Trial]: New treatment modalities for pediatric patients with DMG and other incurable CNS cancers are needed due to the limited efficacy of conventional treatments. While the efficacy of CART, a promising novel approach, has been limited by the immunosuppressive tumour microenvironment of CNS tumours, C7R has been shown to enhance CART survival and function in vitro and in murine models. This phase I trial sought to examine whether C7R could safely enhance the antitumour activity of CART directed against the disialoganglioside, GD2, in children. 11 patients aged 12 months to 21 years (median age = 12.0 years, 45.5% female) with GD2-positive DMG or other progressive GD2-expressing CNS tumours were selected and placed in 3 treatment cohorts based on dosage level according to the standard 3 + 3 design. The first treatment cohort (dose level 0, DL0) received intravenous infusions of GD2.CARTs without the C7R gene, while the subsequent cohorts (DL1 and DL2) received C7R-GD2.CARTs at a baseline dose and an escalated dose. None of the patients receiving GD2.CARTs experienced adverse effects. 88% of patients receiving C7R-GD2.CARTs experienced grade 1 TIAN and 63% experienced grade 1 CRS, all of which resolved with anti-cytokine management with tocilizumab or anakinra. No dose-limiting toxicities were observed in any patient. Among patients with pre-existing neurologic deficits prior to CART, 90% experienced improvement in their baseline symptoms within 3 weeks of treatment. The duration of reduced neurologic deficits was <3 weeks for patients receiving GD2.CARTs, but 86% of patients receiving C7R-GD2.CARTs demonstrated a median duration of 5 months (range, 2-13 months). In the C7R-GD2.CARTs cohort, 88% of patients experienced partial response or stable disease (PR, 13%; SD, 75%).

Image: PD

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