Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.
Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.
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免疫毒素-α CD 40治疗可激活先天性和适应性免疫，并在胶质母细胞瘤模型中产生持久的抗肿瘤应答。
DOI：
10.1126/scitranslmed.abn5649
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发表时间：
2023-02-08
影响因子：
17.1
通讯作者：
Chandramohan, Vidyalakshmi
中科院分区：
文献类型：
--
作者：
Parker, Scott;McDowall, Charlotte;Sanchez-Perez, Luis;Osorio, Cristina;Duncker, Patrick C.;Briley, Aaron;Swartz, Adam M.;Herndon, 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
d2c7免疫毒素（IT）是一种针对野生型表皮生长因子受体（EGFR）和突变型EGFR变体III （EGFRvIII）蛋白的双特异性IT，在胶质母细胞瘤患者亚群中显示出令人鼓舞的生存结果。我们假设胶质母细胞瘤的免疫抑制限制了D2C7-IT的疗效。为了提高应答率和逆转免疫抑制，我们将D2C7-IT肿瘤细胞杀伤与αCD40抗原提呈细胞共刺激相结合。在小鼠胶质瘤模型中，单次瘤内注射D2C7-IT+αCD40治疗，激活小胶质细胞和巨噬细胞的促炎表型，促进肿瘤特异性CD8+ T细胞的长期免疫，并产生治愈。D2C7-IT+αCD40处理增加了瘤内具有祖表型的Slamf6+CD8+ T细胞，减少了终末耗尽的CD8+ T细胞。D2C7-IT+αCD40处理刺激瘤内CD8+ T细胞增殖，尽管fty720诱导外周T细胞隔离，但在胶质瘤小鼠中产生治愈。肿瘤转录组分析证实CD40上调、模式识别受体、细胞衰老和免疫反应通路激活是D2C7-IT+αCD40抗肿瘤反应的驱动因素。为了确定潜在的翻译，免疫组织化学染色证实了CD40在人GBM组织切片中的表达。这些有希望的临床前数据使我们能够启动D2C7-IT+αhCD40在恶性胶质瘤患者（NCT04547777）中的I期研究，以进一步评估这种治疗在人类中的应用。免疫毒素介导的肿瘤细胞杀伤和α cd40介导的免疫细胞激活在脑肿瘤模型中产生治愈作用。
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 upregulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. In order to determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase I study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans. Immunotoxin-mediated tumor cell killing and αCD40-mediated immune cell activation generate cures in brain tumor models.
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影响因子：
4.4
作者：
Buhtoiarov, IN;Lum, H;Rakhmilevich, AL
通讯作者：
Rakhmilevich, AL
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
影响因子：
4.6
作者：
Goedhart J;Luijsterburg MS
通讯作者：
Luijsterburg MS
影响因子：
15.9
作者：
Chuntova, Pavlina;Chow, Frances;Okada, Hideho
通讯作者：
Okada, Hideho
DOI：
10.1126/science.1198443
发表时间：
2011-03-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Beatty GL;Chiorean EG;Fishman MP;Saboury B;Teitelbaum UR;Sun W;Huhn RD;Song W;Li D;Sharp LL;Torigian DA;O'Dwyer PJ;Vonderheide RH
通讯作者：
Vonderheide RH