Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma
Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell lymphoma
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DOI：
10.1080/2162402x.2019.1676615
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发表时间：
2019-10-24
期刊：
影响因子：
7.2
通讯作者：
Mason, Nicola J.
中科院分区：
文献类型：
--
作者：
Panjwani, M. Kazim;Atherton, Matthew J.;Mason, Nicola J.
多项啮齿动物和灵长类动物的临床前研究已经将CAR - T细胞推向了临床。然而，没有一个单一的模型能准确地反映有效的CAR - T治疗在人类癌症患者中的挑战。为了评估旨在克服持久肿瘤消除障碍的下一代CAR - T细胞的有效性，我们开发了一个系统来评估患有自发性癌症的宠物狗的CAR - T细胞。在这里，我们报告了这一系统和使用CAR - T细胞治疗犬弥漫性大B细胞淋巴瘤（DLBCL）的试点试验的结果。我们设计并制造了靶向cd20的第二代犬CAR - T细胞，用于体外和体内功能评估，使用慢载体与人类CAR - T细胞制造平行。对5只接受CAR - T治疗的DLBCL犬进行了首次物种试验。犬CAR - T细胞以抗原特异性的方式起作用并杀死CD20+靶标。然而，注射后可检测到循环中的CAR - T细胞，犬抗小鼠抗体（CAMA）的诱导与CAR - T细胞丢失有关。CAR - T细胞治疗后观察到CD20+肿瘤的特异性选择压力，最终导致抗原逃逸和CD20疾病的出现。患者生存时间与体外产物扩张相关。改变产品制造提高了转导效率，并倾向于犬CAR - T细胞的记忆样表型。使用慢载体制造功能性犬CAR - T细胞是可行的。与有效的CAR - T细胞疗法存在类似的挑战，这表明它们在为未来的人体临床试验设计提供信息方面具有相关性。
Multiple rodent and primate preclinical studies have advanced CAR T cells into the clinic. However, no single model accurately reflects the challenges of effective CAR T therapy in human cancer patients. To evaluate the effectiveness of next-generation CAR T cells that aim to overcome barriers to durable tumor elimination, we developed a system to evaluate CAR T cells in pet dogs with spontaneous cancer. Here we report on this system and the results of a pilot trial using CAR T cells to treat canine diffuse large B cell lymphoma (DLBCL). We designed and manufactured CD20-targeting, second-generation canine CAR T cells for functional evaluation in vitro and in vivo using lentivectors to parallel human CAR T cell manufacturing. A first-in-species trial of five dogs with DLBCL treated with CAR T was undertaken. Canine CAR T cells functioned in an antigen-specific manner and killed CD20+ targets. Circulating CAR T cells were detectable post-infusion, however, induction of canine anti-mouse antibodies (CAMA) was associated with CAR T cell loss. Specific selection pressure on CD20+ tumors was observed following CAR T cell therapy, culminating in antigen escape and emergence of CD20-disease. Patient survival times correlated with ex vivo product expansion. Altering product manufacturing improved transduction efficiency and skewed toward a memory-like phenotype of canine CAR T cells. Manufacturing of functional canine CAR T cells using a lentivector is feasible. Comparable challenges to effective CAR T cell therapy exist, indicating their relevance in informing future human clinical trial design.