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- Title
Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.
- Authors
Parker, Scott; McDowall, Charlotte; Sanchez-Perez, Luis; Osorio, Cristina; Duncker, Patrick C.; Briley, Aaron; Swartz, Adam M.; Herndon II, 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
- 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. Slamming GBM with T cells: An immunotoxin (IT), D2C7-IT, has demonstrated efficacy in a subset of patients with glioblastoma (GBM) but has been limited due to the immunosuppressive tumor microenvironment. To improve response to treatment, Parker et al. have combined D2C7-IT with anti-CD40 treatment to treat and cure glioma-bearing mice. They found that this treatment increased intratumoral Slamf6+CD8+ T cells, stimulated CD8+ T cell proliferation, and decreased terminally exhausted CD8+ T cells. In addition, they demonstrate that CD40 expression is present in GBM tissue from patients, which has warranted further evaluation in a phase I clinical trial (NCT04547777). —DH
- Subjects
EPIDERMAL growth factor receptors; MICROGLIA; NATURAL immunity; PATTERN perception receptors; GLIOBLASTOMA multiforme; GLIOMAS
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 682, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abn5649