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

• Published in: Science translational medicine 2023-02, Vol.15 (682), p.eabn5649-eabn5649
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animal models; Animals; Antigen-presenting cells; Antitumor activity; Brain Neoplasms - therapy; Brain tumors; CD40 antigen; CD8 antigen; CD8-Positive T-Lymphocytes; Cell culture; Cell Line, Tumor; Cell proliferation; Epidermal growth factor receptors; ErbB Receptors - metabolism; FTY720; Glioblastoma; Glioblastoma - pathology; Glioma; Glioma cells; Humans; Immunohistochemistry; Immunosuppression; Immunotoxins; Immunotoxins - genetics; Inflammation; Lymphocytes; Lymphocytes T; Macrophages; Mice; Microglia; Pattern recognition receptors; Phenotypes; Senescence; Transcriptomes
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.abn5649

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.