Department of Mathematics, Spelman College, Atlanta, GA, USA.
Department of Mathematics, University of Michigan, Ann Arbor, MI, USA.
NPJ Syst Biol Appl. 2024 Sep 28;10(1):105. doi: 10.1038/s41540-024-00435-4.
As an adoptive cellular therapy, Chimeric Antigen Receptor T cell (CAR T cell) therapy has shown remarkable success in hematological malignancies but only limited efficacy against solid tumors. Compared with blood cancers, solid tumors present a series of challenges that ultimately combine to neutralize the function of CAR T cells. These challenges include, but are not limited to, antigen heterogeneity - variability in the expression of the antigen on tumor cells, as well as trafficking and infiltration into the solid tumor tissue. A critical question for solving the heterogeneity problem is whether CAR T therapy induces bystander effects, such as antigen spreading. Antigen spreading occurs when CAR T cells activate other endogenous antitumor CD8 T cells against antigens that were not originally targeted. In this work, we develop a mathematical model of CAR T cell therapy for solid tumors that considers both antigen heterogeneity and bystander effects. Our model is based on in vivo treatment data that includes a mixture of target antigen-positive and target antigen-negative tumor cells. We use our model to simulate large cohorts of virtual patients to better understand the relationship involving bystander killing. We also investigate several strategies for enhancing bystander effects, thus increasing CAR T cell therapy's overall efficacy for solid tumors.
嵌合抗原受体 T 细胞（CAR T 细胞）疗法作为一种过继细胞疗法，在血液恶性肿瘤方面取得了显著的成功，但对实体瘤的疗效有限。与血液癌症相比，实体瘤存在一系列挑战，这些挑战最终共同中和了 CAR T 细胞的功能。这些挑战包括但不限于抗原异质性——肿瘤细胞上抗原表达的可变性，以及在实体肿瘤组织中的运输和浸润。解决异质性问题的一个关键问题是 CAR T 疗法是否诱导旁观者效应，例如抗原扩散。当 CAR T 细胞激活针对原本未靶向抗原的其他内源性抗肿瘤 CD8 T 细胞时，就会发生抗原扩散。在这项工作中，我们为实体瘤的 CAR T 细胞疗法开发了一个数学模型，该模型同时考虑了抗原异质性和旁观者效应。我们的模型基于包括靶抗原阳性和靶抗原阴性肿瘤细胞混合物的体内治疗数据。我们使用我们的模型来模拟大量虚拟患者，以更好地理解涉及旁观者杀伤的关系。我们还研究了几种增强旁观者效应的策略，从而提高 CAR T 细胞疗法治疗实体瘤的总体疗效。
