Nivolumab in the Treatment of Recurrent or Refractory Pediatric Brain Tumors: A Single Institutional Experience

Abstract

Successful use of immune checkpoint inhibitors in a variety of cancers has generated interest in using this approach in pediatric brain tumors. We performed a retrospective review of 10 consecutive children (6 boys, 4 girls; ages, 2 to 17 y), with recurrent or refractory pediatric brain tumors (5 high-grade glioma, 1 lowgrade glioma, pineoblastoma, medulloblastoma, ependymoma, and CNS embryonal tumor, NOS) treated at Rady Children's Hospital San Diego from 2015 to 2017 with the immune checkpoint inhibitor nivolumab (3 mg/kg every 2 wk). Eight of 10 patients received prior chemotherapy and 9 radiation therapy. Nine patients had radiographic disease progression (median, 2.5 doses). Median time to progression was 5.5 weeks (1.6 to 24 wk). Three patients (2 with high-grade glioma, 1 with CNS embryonal tumor NOS) showed a partial response to treatment at the primary tumor site and 2 of 3 had progression of metastatic disease. Grade 2 toxicities were observed without dose limiting side effects. Tumor mutation burden (TMB) was low to intermediate (median, 1.3; range, 0 to 6.3). Median survival for PD-L1 positive patients was 13.7 weeks versus 4.2 weeks for PD-L1 negative patients (ρ = 0.08) nivolumab was well tolerated in our series of pediatric recurrent brain tumors with some transient partial responses in patients with positive PD-L1 expression and higher TMB. Our findings suggest that the use of immune checkpoint inhibitors in pediatric brain tumor patients should be limited to those with elevated PD-L1 expression and TMB.

T lymphocyte-targeted immune checkpoint modulation in glioma

“…A series of 10 patients with recurrent or refractory pediatric brain tumors including pineoblastoma, medulloblastoma, ependymoma and CNS embryonal showed transient partial responses in patients with PD-L1 expression and higher tumor mutation burden. 146 A study of the immune checkpoint inhibitor nivolumab is ongoing in patients with select rare CNS cancers (NCT03173950). Additionally, responses to immune checkpoint blockade have been reported, although rarely, in other primary CNS malignancies such as meningioma and primary CNS lymphoma [147][148][149] Initial studies using single agent immune modulators in GBM have been mostly unsuccessful, thereby providing a stronger rationale for the consideration of combinational regimens.…”

Immunohistochemical evaluation of immune cell infiltration in canine gliomas

“…However, a hallmark of cancer is evasion of the immune system, and gliomas are particularly adept at such evasion. 23,28,82 Important components of immune evasion by gliomas in humans include recruitment of regulatory T cells (Tregs) to the tumor and polarization of tumor-associated macrophages toward an M2 phenotype. 54,56,83 The primary function of Tregs is to inhibit the functions of effector immune cells, which prevents the development of autoimmunity in healthy individuals.…”

Immunotherapy in Pediatric Solid Tumors—A Systematic Review

“…In a retrospective review of 10 children with recurrent or refractory brain tumors treated with nivolumab, 9 patients had radiographic disease progression. Three patients had partial response at the primary tumor site, of whom two had progression of metastatic disease [42]. In other small studies of nivolumab treatment in pediatric brain tumor patients, results were mixed.…”