The latest medical research on Neurosurgery

Treatment for pediatric posterior fossa group A (PFA) ependymoma with gain of chromosome 1q (1q+) has not improved over the past decade owed partially to lack of clinically relevant models. We described the first two 1q+ PFA cell lines, which has significantly enhanced our understanding of PFA tumor biology and provided a tool to identify specific 1q+ PFA therapies. However, cell lines do not accurately replicate the tumor microenvironment. Our present goal is to establish patient-derived xenograft (PDX) mouse models.

Disaggregated tumors from two 1q+ PFA patients were injected into the flanks of NSG mice. Flank tumors were then transplanted into the 4th ventricle or lateral ventricle of NSG mice. Characterization of intracranial tumors was performed using imaging, histology, and bioinformatics.

MAF-811_XC and MAF-928_XC established intracranially within the 4th ventricle and retained histological, methylomic, and transcriptomic features of primary patient tumors. We tested the feasibility of treating PDX mice with fractionated radiation or chemotherapy. Mice tolerated radiation despite significant tumor burden, and follow-up imaging confirmed radiation can reduce tumor size. Treatment with Fluorouracil reduced tumor size but did not appear to prolong survival.

MAF-811_XC and MAF-928_XC are novel, authentic, and reliable models for studying 1q+ PFA1 in vivo. Given the successful response to radiation, these models will be advantageous for testing clinically relevant combination therapies to develop future clinical trials for this high-risk subgroup of pediatric ependymoma.

Glioblastoma survival remains unchanged despite continuing therapeutic innovation. Herein, we aim to 1) develop CAR-T cells with a specificity to a unique antigen, carbonic anhydrase IX (CAIX), which is expressed in the hypoxic microenvironment characteristic of glioblastoma, and 2) demonstrate its efficacy with limited off-target effects.

First we demonstrated expression of CAIX in patient-derived glioblastoma samples and available databases. CAR-T cells were generated against CAIX and efficacy was assessed in four glioblastoma cell lines and two glioblastoma stem cell lines. Cytotoxicity of anti-CAIX CAR-T cells was assessed via IFN-γ, TNF-α, and IL-2 levels when co-cultured with tumor cells. Finally, we assessed efficacy of direct intra-tumoral injection of the anti-CAIX CAR-T cells on an in vivo xenograft mouse model using the U251 fluorescent cell line. Tumor infiltrating lymphocyte analyses were performed.

We confirm that CAIX is highly expressed in glioblastoma from patients. We demonstrate that CAIX is a suitable target for CAR-T therapy using anti-CAIX CAR-T cells against glioblastoma in vitro and in vivo. In our mouse model, a 20% cure rate was observed without detectable systemic effects.

By establishing the specificity of CAIX under hypoxic conditions in glioblastoma and highlighting its efficacy as a target for CAR-T therapy, our data suggest that anti-CAIX CAR-T may be a promising strategy to treat glioblastoma. Direct intra-tumoral injection increases anti-CAIX CAR-T potency while limiting its off-target effects.