Bard College, 30 Campus Road, Annandale-on-Hudson, NY 12504, USA.
Cells. 2022 Oct 9;11(19):3165. doi: 10.3390/cells11193165.
Chimeric antigen receptor (CAR) T-cell therapy has been successful in treating liquid tumors but has had limited success in solid tumors. This work examines unanswered questions regarding CAR T-cell therapy using computational modeling, such as, what percentage of the tumor must express cancer-associated antigens for treatment to be successful? The model includes cancer cell and vascular and CAR T-cell modules that interact with each other. We compare two different models of antigen expression on tumor cells, binary (in which cancer cells are either susceptible or are immune to CAR T-cell therapy) and gradated (where each cancer cell has a probability of being killed by a CAR T-cell). We vary the antigen expression levels within the tumor and determine how effective each treatment is for the two models. The simulations show that the gradated antigen model eliminates the tumor under more parameter values than the binary model. Under both models, shielding, in which the low/non-antigen-expressing cells protect high antigen-expressing cells, reduced the efficacy of CAR T-cell therapy. One prediction is that a combination of CAR T-cell therapies that targets the general population of cells as well as one that specifically targets cancer stem cells should increase its efficacy.
嵌合抗原受体 (CAR) T 细胞疗法已成功用于治疗液体肿瘤，但在实体肿瘤中的疗效有限。本研究通过计算建模来研究 CAR T 细胞疗法的未解决问题，例如，肿瘤必须有多大比例表达癌相关抗原才能使治疗成功？该模型包括癌细胞、血管和 CAR T 细胞模块，它们相互作用。我们比较了两种不同的肿瘤细胞抗原表达模型，二进制（其中癌细胞要么易受 CAR T 细胞治疗影响，要么对其具有免疫力）和梯度（每个癌细胞都有被 CAR T 细胞杀死的概率）。我们在肿瘤内改变抗原表达水平，并确定两种模型中每种治疗的效果如何。模拟结果表明，梯度抗原模型在更多参数值下消除肿瘤，比二进制模型更有效。在这两种模型下，屏蔽作用（低/非抗原表达细胞保护高抗原表达细胞）降低了 CAR T 细胞疗法的疗效。一个预测是，针对细胞总体以及专门针对癌症干细胞的 CAR T 细胞疗法的联合治疗应该会提高其疗效。
