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Parker, Scott; McDowall, Charlotte; Sanchez-Perez, Luis; Osorio, Cristina; Duncker, Patrick C; Briley, Aaron; Swartz, Adam M; Herndon, 2nd, James E; Yu, Yen-Rei A; McLendon, Roger E; Tedder, Thomas F; Desjardins, Annick; Ashley, David M; Gunn, Michael Dee; Enterline, David S; Knorr, David A; Pastan, Ira H; Nair, Smita K; Bigner, Darell D; Chandramohan, Vidyalakshmi
Science translational medicine, 02/2023, Volume: 15, Issue: 682Journal Article
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 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.
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