Guillem Pascual-Pasto, Brendan McIntyre, Anna M Giudice, Fatemeh Alikarami, Amanda Morrissey, Stephanie Matlaga, Ted J Hofmann, Victor Burgueño, Kyra Harvey, Daniel Martinez, Amish C Shah, Jessica B Foster, Jennifer Pogoriler, Ralph C Eagle, Angel M Carcaboso, Carol L Shields, Ann-Marie Leahey, Kristopher R Bosse
{"title":"用局部和全身性 CAR T 细胞靶向眼内和中枢神经系统转移性视网膜母细胞瘤上的 GPC2。","authors":"Guillem Pascual-Pasto, Brendan McIntyre, Anna M Giudice, Fatemeh Alikarami, Amanda Morrissey, Stephanie Matlaga, Ted J Hofmann, Victor Burgueño, Kyra Harvey, Daniel Martinez, Amish C Shah, Jessica B Foster, Jennifer Pogoriler, Ralph C Eagle, Angel M Carcaboso, Carol L Shields, Ann-Marie Leahey, Kristopher R Bosse","doi":"10.1158/1078-0432.CCR-24-0221","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy.</p><p><strong>Experimental design: </strong>GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models.</p><p><strong>Results: </strong>Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival.</p><p><strong>Conclusions: </strong>GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326963/pdf/","citationCount":"0","resultStr":"{\"title\":\"Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells.\",\"authors\":\"Guillem Pascual-Pasto, Brendan McIntyre, Anna M Giudice, Fatemeh Alikarami, Amanda Morrissey, Stephanie Matlaga, Ted J Hofmann, Victor Burgueño, Kyra Harvey, Daniel Martinez, Amish C Shah, Jessica B Foster, Jennifer Pogoriler, Ralph C Eagle, Angel M Carcaboso, Carol L Shields, Ann-Marie Leahey, Kristopher R Bosse\",\"doi\":\"10.1158/1078-0432.CCR-24-0221\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Retinoblastoma is the most common intraocular malignancy in children. 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引用次数: 0
摘要
目的:视网膜母细胞瘤是儿童最常见的眼内恶性肿瘤:视网膜母细胞瘤是儿童最常见的眼内恶性肿瘤。虽然新的化疗方法提高了眼部救治率,但对于眼内难治性疾病和转移性疾病患者,仍需要新的疗法。以glypican-2(GPC2)为靶点的嵌合抗原受体(CAR)T细胞是一种潜在的新治疗策略:实验设计:我们在视网膜母细胞瘤患者样本和细胞模型中研究了GPC2的表达及其受E2F1转录因子的调控。在体外,我们对具有不同协同刺激结构域(4-1BB 和 CD28)的 GPC2 CAR T 细胞进行了功能研究。在体内,我们在眼内和脑外人类视网膜母细胞瘤异种移植模型中评估了局部和全身给药 GPC2 CAR T 细胞的疗效:结果:视网膜母细胞瘤肿瘤(而非健康视网膜组织)表达细胞表面GPC2,这种肿瘤特异性表达由E2F1驱动。具有4-1BB协同刺激的GPC2定向CAR(GPC2.BBz)优于具有CD28刺激域的CAR(GPC2.28z),能有效诱导视网膜母细胞瘤细胞毒性并增强T细胞增殖和多功能性。在体内,与对照CD19或GPC2.28z CAR相比,GPC2.BBz CAR具有更强的持久性,可导致肿瘤显著消退。在眼内模型中,GPC2.BBz CAR T细胞在玻璃体内或全身输注后能有效地迁移到肿瘤患者的眼睛中,显著延长眼部存活时间。在中枢神经系统(CNS)视网膜母细胞瘤模型中,经静脉注射或全身给药的GPC2.BBz CAR T细胞在视网膜母细胞瘤累及的中枢神经系统组织中被激活,导致肿瘤强力消退,并大大延长了小鼠的总体生存期:结论:GPC2 引导的 CAR T 细胞对眼内和中枢神经系统转移性视网膜母细胞瘤有效。
Targeting GPC2 on Intraocular and CNS Metastatic Retinoblastomas with Local and Systemic Delivery of CAR T Cells.
Purpose: Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy.
Experimental design: GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models.
Results: Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival.
Conclusions: GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.