Mork Family Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
Hum Gene Ther. 2023 Nov;34(21-22):1145-1161. doi: 10.1089/hum.2022.068. Epub 2023 Apr 20.
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies but has yet to achieve similar success in solid tumors due to a lack of persistence and function in the tumor microenvironment. We previously reported the augmentation of CAR T cell therapy in an engineered solid tumor model through the secretion of anti-PD-1 single-chain fragment variable region (scFv), as shown by enhanced CAR T cell antitumor efficacy, expansion, and vitality. We have since improved the platform to create a superior cellular product-CAR T cells secreting single-chain trimeric 4-1BB ligand fused to anti-PD-1 scFv (αPD1-41BBL). 4-1BB signaling promotes cytotoxic T lymphocyte proliferation and survival but targeting 4-1BB with agonist antibodies in the clinic has been hindered by low antitumor activity and high toxicity. CAR T cells using 4-1BB endodomain for costimulatory signals have demonstrated milder antitumor response and longer persistence compared to CAR T cells costimulated by CD28 endodomain. We have, for the first time, engineered CD28-costimulated CAR T cells to secrete a fusion protein containing the soluble trimeric 4-1BB ligand. and , CAR19.αPD1-41BBL T cells exhibited reduced inhibitory receptor upregulation, enhanced persistence and proliferation, and a less differentiated memory status compared to CAR T cells without additional 4-1BB:4-1BBL costimulation. Accordingly, CAR19.αPD1-41BBL T cell-treated mice displayed significantly improved tumor growth control and overall survival. Spurred on by our preclinical success targeting CD19 as a model antigen, we produced mesothelin-targeting CAR T cells and confirmed the enhanced solid tumor efficacy of αPD1-41BBL-secreting CAR T cells.
嵌合抗原受体 (CAR) T 细胞疗法已经改变了血液恶性肿瘤的治疗方法,但由于在肿瘤微环境中缺乏持久性和功能,尚未在实体瘤中取得类似的成功。我们之前报道过通过分泌抗 PD-1 单链片段可变区 (scFv) 来增强 CAR T 细胞疗法在工程化实体瘤模型中的作用,这表现为增强了 CAR T 细胞的抗肿瘤疗效、扩增和活力。此后,我们改进了该平台,创造了一种优越的细胞产品——分泌与抗 PD-1 scFv 融合的单链三聚体 4-1BB 配体的 CAR T 细胞 (αPD1-41BBL)。4-1BB 信号促进细胞毒性 T 淋巴细胞的增殖和存活,但在临床中使用激动性抗体靶向 4-1BB 受到抗肿瘤活性低和毒性高的阻碍。与由 CD28 内域共刺激的 CAR T 细胞相比,使用 4-1BB 内域作为共刺激信号的 CAR T 细胞显示出更温和的抗肿瘤反应和更长的持久性。我们首次设计了 CD28 共刺激的 CAR T 细胞来分泌含有可溶性三聚体 4-1BB 配体的融合蛋白。与没有额外的 4-1BB:4-1BBL 共刺激的 CAR T 细胞相比,CAR19.αPD1-41BBL T 细胞表现出抑制性受体上调减少、持久性和增殖增强以及分化记忆状态减少。因此,CAR19.αPD1-41BBL T 细胞治疗的小鼠显示出显著改善的肿瘤生长控制和总生存。受到我们以 CD19 作为模型抗原进行的临床前成功的鼓舞,我们产生了间皮素靶向 CAR T 细胞,并证实了分泌 αPD1-41BBL 的 CAR T 细胞在实体瘤中的疗效增强。
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