Mathematical Modeling Insights into Improving CAR T cell Therapy for Solid Tumors: Antigen Heterogeneity and Bystander Effects
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| Main Authors: | , , , , |
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| Format: | Preprint |
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2023
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| _version_ | 1866916451120578560 |
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| author | Kara, Erdi Jackson, T. L. Jones, Chartese McGee II, Reginald L. Sison, Rockford |
| author_facet | Kara, Erdi Jackson, T. L. Jones, Chartese McGee II, Reginald L. Sison, Rockford |
| contents | 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 unique set of challenges that ultimately neutralize the function of CAR T-cells. One such barrier is antigen heterogeneity - variability in the expression of the antigen on tumor cells. Success of CAR T-cell therapy in solid tumors is unlikely unless almost all the tumor cells express the specific antigen that CAR T-cells target. 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 takes into consideration 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 gain a better understanding of the relationship between bystander killing. We also investigate several strategies for enhancing the bystander effect and thus increasing the overall efficacy of CAR T-cell therapy for solid tumor. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2307_05606 |
| institution | arXiv |
| publishDate | 2023 |
| record_format | arxiv |
| spellingShingle | Mathematical Modeling Insights into Improving CAR T cell Therapy for Solid Tumors: Antigen Heterogeneity and Bystander Effects Kara, Erdi Jackson, T. L. Jones, Chartese McGee II, Reginald L. Sison, Rockford Tissues and Organs 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 unique set of challenges that ultimately neutralize the function of CAR T-cells. One such barrier is antigen heterogeneity - variability in the expression of the antigen on tumor cells. Success of CAR T-cell therapy in solid tumors is unlikely unless almost all the tumor cells express the specific antigen that CAR T-cells target. 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 takes into consideration 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 gain a better understanding of the relationship between bystander killing. We also investigate several strategies for enhancing the bystander effect and thus increasing the overall efficacy of CAR T-cell therapy for solid tumor. |
| title | Mathematical Modeling Insights into Improving CAR T cell Therapy for Solid Tumors: Antigen Heterogeneity and Bystander Effects |
| topic | Tissues and Organs |
| url | https://arxiv.org/abs/2307.05606 |