{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE327nnn/GSE327275/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327275"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Immune activation and biomarkers of response to EGFR-targeted antibody-toxin therapy in a Phase 1 trial of recurrent malignant glioma","description":"Recurrent glioblastoma (rGBM) has a dismal prognosis and is frequently characterized by epidermal growth factor receptor (EGFR) alterations. D2C7-ATC is a recombinant antibody-toxin conjugate (ATC) targeting wild-type EGFR and mutant EGFR variant III (EGFRvIII). We conducted a single-arm, single-site, open-label Phase 1 trial evaluating a single infusion of D2C7-ATC via convection-enhanced delivery in the enhancing disease of 81 patients with biopsy-confirmed recurrent malignant glioma. The primary objective of the trial was to determine the toxicity and the recommended phase 2 dose (RP2D) of D2C7-ATC. Secondary objectives included the description of overall survival (OS) and the assessment of the association between EGFR expression and OS. The median OS [mOS] was 9.5 months among 81 patients with recurrent malignant glioma, which included 43 patients in the dose-escalation stage (40 to 35,032 ng/mL) and 38 in the dose-expansion stage (at the RP2D of 6,920 ng/mL). Among patients with isocitrate dehydrogenase (IDH) wild-type (wt) rGBM (N=72), 35% (N=25), 24% (N=17), and 11% (N=8) survived longer than 12, 15, and 20 months, respectively, and three achieved durable radiographic partial responses lasting 54, 34, and 28 months. D2C7-ATC was generally well tolerated, with mainly grade 1–2 treatment-related adverse events (67%). Adverse events were predominantly neurologic and were associated with the location of the infused, enhancing recurrent tumor as well as secondary reactive peritumoral inflammation. The maximum tolerated dose was exceeded at 35,032 ng/mL after two patients experienced dose-limiting toxicity (grade 4 cerebral edema, N=1; grade 3 dysphasia, N=1). In the group of IDHwt rGBM patients with available tumor and plasma samples (N=27), univariate analyses identified survival-associated biomarkers, including tumor EGFR expression, a tumor inflammatory gene signature (CXCL8, CCL20, IL1A, CSF2, CCL2, IL6, IL1R1), and circulating cytokines (MIP-3b, PD-L1, GM-CSF, IL-8, VEGF). Importantly, IDHwt rGBM patients with low EGFR expression in pre-treatment tumor had a mOS of 13 months (P = 0.09), while those with low IL-18 in post-treatment plasma had a mOS of 16.6 months (P = 0.0008). The trial met all primary and secondary objectives. Reverse translational studies in the CT2A-EGFRvIII syngeneic model implicated neutrophils and neutrophil extracellular traps in mediating antitumor responses. These findings indicate that EGFR-targeted D2C7-ATC therapy prolongs survival in a subset of patients with IDHwt rGBM via intratumoral and systemic immune activation, and provide a mechanistic rationale for further evaluation in a larger cohort of patients with IDHwt rGBM. ClinicalTrials.gov registration: NCT02303678.","dates":{"publication":"2026/09/09"},"accession":"GSE327275","cross_references":{"GSM":["GSM9652670","GSM9652660","GSM9652671","GSM9652672","GSM9652661","GSM9652673","GSM9652662","GSM9652651","GSM9652656","GSM9652667","GSM9652657","GSM9652668","GSM9652669","GSM9652658","GSM9652659","GSM9652663","GSM9652652","GSM9652674","GSM9652653","GSM9652664","GSM9652665","GSM9652654","GSM9652666","GSM9652655"],"GPL":["34284"],"GSE":["327275"],"taxon":["Homo sapiens"]}}