作为一种过继性细胞疗法，嵌合抗原受体T细胞（CAR T细胞）疗法在血液恶性肿瘤方面取得了显着的成功，但对实体瘤的疗效有限。与血癌相比，实体瘤面临一系列挑战，最终会抵消 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变异性，以及实体瘤组织中抗原的运输和浸润。解决异质性问题的一个关键问题是CAR T疗法是否会引起旁观者效应，例如抗原扩散。当 CAR T 细胞激活其他内源性抗肿瘤 CD8 T 细胞来对抗最初不是目标的抗原时，就会发生抗原扩散。在这项工作中，我们开发了一种实体瘤 CAR T 细胞治疗的数学模型，该模型考虑了抗原异质性和旁观者效应。我们的模型基于体内治疗数据，其中包括靶抗原阳性和靶抗原阴性肿瘤细胞的混合物。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戮的关系。我们还研究了几种增强旁观者效应的策略，从而提高 CAR T 细胞疗法对实体瘤的整体疗效。© 2024。作者。

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.© 2024. The Author(s).