Henze Janina, Tacke Frank, Hardt Olaf, Alves Frauke, Al Rawashdeh Wa'el
University Medical Center Göttingen, Translational Molecular Imaging, Institute for Diagnostic and Interventional Radiology & Clinic for Hematology and Medical Oncology, 37075 Göttingen, Lower Saxony, Germany.
Miltenyi Biotec B.V. & Co. KG, R&D Reagents, Bergisch Gladbach, 51429 North Rhine-Westphalia, Germany.
Cancers (Basel). 2020 May 28;12(6):1389. doi: 10.3390/cancers12061389.
Pancreatic cancer has the worst prognosis and lowest survival rate among all types of cancers and thus, there exists a strong need for novel therapeutic strategies. Chimeric antigen receptor (CAR)-modified T cells present a new potential option after successful FDA-approval in hematologic malignancies, however, current CAR T cell clinical trials in pancreatic cancer failed to improve survival and were unable to demonstrate any significant response. The physical and environmental barriers created by the distinct tumor microenvironment (TME) as a result of the desmoplastic reaction in pancreatic cancer present major hurdles for CAR T cells as a viable therapeutic option in this tumor entity. Cancer cells and cancer-associated fibroblasts express extracellular matrix molecules, enzymes, and growth factors, which can attenuate CAR T cell infiltration and efficacy. Recent efforts demonstrate a niche shift where targeting the TME along CAR T cell therapy is believed or hoped to provide a substantial clinical added value to improve overall survival. This review summarizes therapeutic approaches targeting the TME and their effect on CAR T cells as well as their outcome in preclinical and clinical trials in pancreatic cancer.
在所有类型的癌症中，胰腺癌的预后最差，生存率最低，因此，迫切需要新的治疗策略。嵌合抗原受体（CAR）修饰的T细胞在血液系统恶性肿瘤中获得FDA成功批准后，成为一种新的潜在选择，然而，目前在胰腺癌中进行的CAR T细胞临床试验未能提高生存率，也未能显示出任何显著反应。胰腺癌中促结缔组织增生反应导致独特的肿瘤微环境（TME）形成的物理和环境障碍，是CAR T细胞作为该肿瘤实体可行治疗选择的主要障碍。癌细胞和癌症相关成纤维细胞表达细胞外基质分子、酶和生长因子，这些可减弱CAR T细胞的浸润和疗效。最近的研究表明，有一种生态位转变，即人们相信或希望在CAR T细胞治疗的同时靶向TME能为提高总生存率提供实质性的临床附加值。本综述总结了靶向TME的治疗方法及其对CAR T细胞的影响，以及它们在胰腺癌临床前和临床试验中的结果。
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