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Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.

ABSTRACT: D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8⁺ T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6⁺CD8⁺ T cells with a progenitor phenotype and decreased terminally exhausted CD8⁺ T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8⁺ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.

SUBMITTER: Parker S

PROVIDER: S-EPMC10440725 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.

Parker Scott S McDowall Charlotte C Sanchez-Perez Luis L Osorio Cristina C Duncker Patrick C PC Briley Aaron A Swartz Adam M AM Herndon James E JE Yu Yen-Rei A YA McLendon Roger E RE Tedder Thomas F TF Desjardins Annick A Ashley David M DM Gunn Michael Dee MD Enterline David S DS Knorr David A DA Pastan Ira H IH Nair Smita K SK Bigner Darell D DD Chandramohan Vidyalakshmi V

Science translational medicine 20230208 682

D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a sin ...[more]

PMID: 36753564

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Dataset Information

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.

Publications

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.

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