Lin Heather K, Blake Dejah A, Liu Tongrui, Freeman Ruby, Lesinski Gregory B, Yang Lily, Rafiq Sarwish
Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
Mol Ther Oncol. 2024 Sep 2;32(4):200868. doi: 10.1016/j.omton.2024.200868. eCollection 2024 Dec 19.
Pancreatic cancer is an aggressive malignancy with a 5-year survival rate of 13% that remains refractory to current immunotherapies, such as chimeric antigen receptor (CAR) T cells. These engineered cells can produce robust anti-tumor responses but require a reliable tumor-associated antigen (TAA) target. Here, we describe the retained ectodomain of Muc16, Muc16CD, as a novel TAA for targeting by CAR T cell therapy in pancreatic cancer. We establish clinically relevant, endogenous Muc16 and Muc16CD expression in pancreatic tumor tissues for CAR T cell targeting. Muc16CD-directed CAR T cells can both recognize and activate in a polyfunctional manner in response to patient-derived pancreatic tumor cells. Last, we demonstrate that Muc16CD-directed CAR T cells can elicit an anti-tumor response with significantly enhanced tumor control and survival benefits in a pancreatic tumor model. Overall, these findings demonstrate the utility of Muc16CD-targeted CAR T cell therapy in the novel setting of pancreatic cancer.
胰腺癌是一种侵袭性恶性肿瘤，5年生存率为13%，对目前的免疫疗法（如嵌合抗原受体（CAR）T细胞）仍然难治。这些工程细胞可产生强大的抗肿瘤反应，但需要可靠的肿瘤相关抗原（TAA）靶点。在此，我们将Muc16的保留胞外域Muc16CD描述为一种新型TAA，用于在胰腺癌中通过CAR T细胞疗法进行靶向治疗。我们在胰腺肿瘤组织中建立了与临床相关的内源性Muc16和Muc16CD表达，用于CAR T细胞靶向。Muc16CD导向的CAR T细胞能够以多功能方式识别并激活来自患者的胰腺肿瘤细胞。最后，我们证明Muc16CD导向的CAR T细胞在胰腺肿瘤模型中能够引发抗肿瘤反应，并显著增强肿瘤控制效果和延长生存期。总体而言，这些发现证明了Muc16CD靶向的CAR T细胞疗法在胰腺癌新治疗领域的效用。
