Locoregional Delivery of CAR-T Cells Is Feasible in Pediatric CNS Tumors

HER2 is an attractive target in central nervous system (CNS) tumors, including pediatric tumors, because it is expressed in multiple tumor types and not healthy CNS tissue, but the efficacy of currently available targeted therapeutics is limited in part by the blood–brain barrier. Recent phase I trial data has shown that repeated delivery of chimeric antigen receptor T (CAR-T) cells directly to the tumor site is safe and feasible in adult patients with glioblastoma, prompting Vitanza and colleagues to evaluate the feasibility and tolerability of HER2-targeting CAR-T cells in children and young adults with recurrent or refractory CNS tumors in the ongoing BrainChild-01 trial. Feasibility, tolerability, and correlative data were reported from three patients between the ages of 16 and 26; two had metastatic ependymoma and one had anaplastic astrocytoma. T cells were extracted from each patient and a balanced CD4⁺ and CD8⁺ CAR-T cell product was engineered within target time frames for 2 of 3 patients. All three patients received multiple infusions of CAR-T cells at two different dosing levels delivered intracranially directly to the tumor site. No dose-limiting toxicities were observed, but adverse events reported included headache, pain, and worsening of existing neurologic deficits, with two patients also reporting fever. Analysis of CSF and serum from patients over multiple treatment timepoints did not detect any CAR-T cells but did identify increases in non–CAR-T cell populations in the CSF after CAR-T cell infusion and increased concentrations of several cytokines post-infusion, particularly CXCL10 and CCL2. After completion of the second course of treatment, 2 patients had progressive disease and one had stable disease. This interim analysis of the BrainChild-01 trial provides preliminary evidence of feasibility of locoregional delivery of CAR-T cells in children and young adults with CNS tumors and suggests that correlative CSF markers may be useful in detecting CAR-T cell activity in this setting.

Vitanza NA, Johnson AJ, Wilson AL, Brown C, Yokoyama JK, Künkele A, et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat Med 2021 Jul 12 [Epub ahead of print].

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