Mapping CAR T-Cell Design Space Using Agent-Based Models
Chimeric antigen receptor (CAR) T-cell therapy shows promise for treating liquid cancers and increasingly for solid tumors as well. While potential design strategies exist to address translational challenges, including the lack of unique tumor antigens and the presence of an immunosuppressive tumor...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2022.849363/full |
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| author | Alexis N. Prybutok Jessica S. Yu Jessica S. Yu Joshua N. Leonard Joshua N. Leonard Joshua N. Leonard Joshua N. Leonard Neda Bagheri Neda Bagheri Neda Bagheri Neda Bagheri Neda Bagheri |
| author_facet | Alexis N. Prybutok Jessica S. Yu Jessica S. Yu Joshua N. Leonard Joshua N. Leonard Joshua N. Leonard Joshua N. Leonard Neda Bagheri Neda Bagheri Neda Bagheri Neda Bagheri Neda Bagheri |
| author_sort | Alexis N. Prybutok |
| collection | DOAJ |
| description | Chimeric antigen receptor (CAR) T-cell therapy shows promise for treating liquid cancers and increasingly for solid tumors as well. While potential design strategies exist to address translational challenges, including the lack of unique tumor antigens and the presence of an immunosuppressive tumor microenvironment, testing all possible design choices in vitro and in vivo is prohibitively expensive, time consuming, and laborious. To address this gap, we extended the modeling framework ARCADE (Agent-based Representation of Cells And Dynamic Environments) to include CAR T-cell agents (CAR T-cell ARCADE, or CARCADE). We conducted in silico experiments to investigate how clinically relevant design choices and inherent tumor features—CAR T-cell dose, CD4+:CD8+ CAR T-cell ratio, CAR-antigen affinity, cancer and healthy cell antigen expression—individually and collectively impact treatment outcomes. Our analysis revealed that tuning CAR affinity modulates IL-2 production by balancing CAR T-cell proliferation and effector function. It also identified a novel multi-feature tuned treatment strategy for balancing selectivity and efficacy and provided insights into how spatial effects can impact relative treatment performance in different contexts. CARCADE facilitates deeper biological understanding of treatment design and could ultimately enable identification of promising treatment strategies to accelerate solid tumor CAR T-cell design-build-test cycles. |
| first_indexed | 2024-12-11T01:07:44Z |
| format | Article |
| id | doaj.art-daa0a8a8db0b41cbb9c2873caca33b12 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-11T01:07:44Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-daa0a8a8db0b41cbb9c2873caca33b122022-12-22T01:26:07ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2022-07-01910.3389/fmolb.2022.849363849363Mapping CAR T-Cell Design Space Using Agent-Based ModelsAlexis N. Prybutok0Jessica S. Yu1Jessica S. Yu2Joshua N. Leonard3Joshua N. Leonard4Joshua N. Leonard5Joshua N. Leonard6Neda Bagheri7Neda Bagheri8Neda Bagheri9Neda Bagheri10Neda Bagheri11Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United StatesDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United StatesDepartment of Biology, University of Washington, Seattle, WA, United StatesDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United StatesCenter for Synthetic Biology, Northwestern University, Evanston, IL, United StatesChemistry of Life Processes Institute, Northwestern University, Evanston, IL, United StatesRobert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL, United StatesDepartment of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United StatesDepartment of Biology, University of Washington, Seattle, WA, United StatesCenter for Synthetic Biology, Northwestern University, Evanston, IL, United StatesChemistry of Life Processes Institute, Northwestern University, Evanston, IL, United StatesDepartment of Chemical Engineering, University of Washington, Seattle, WA, United StatesChimeric antigen receptor (CAR) T-cell therapy shows promise for treating liquid cancers and increasingly for solid tumors as well. While potential design strategies exist to address translational challenges, including the lack of unique tumor antigens and the presence of an immunosuppressive tumor microenvironment, testing all possible design choices in vitro and in vivo is prohibitively expensive, time consuming, and laborious. To address this gap, we extended the modeling framework ARCADE (Agent-based Representation of Cells And Dynamic Environments) to include CAR T-cell agents (CAR T-cell ARCADE, or CARCADE). We conducted in silico experiments to investigate how clinically relevant design choices and inherent tumor features—CAR T-cell dose, CD4+:CD8+ CAR T-cell ratio, CAR-antigen affinity, cancer and healthy cell antigen expression—individually and collectively impact treatment outcomes. Our analysis revealed that tuning CAR affinity modulates IL-2 production by balancing CAR T-cell proliferation and effector function. It also identified a novel multi-feature tuned treatment strategy for balancing selectivity and efficacy and provided insights into how spatial effects can impact relative treatment performance in different contexts. CARCADE facilitates deeper biological understanding of treatment design and could ultimately enable identification of promising treatment strategies to accelerate solid tumor CAR T-cell design-build-test cycles.https://www.frontiersin.org/articles/10.3389/fmolb.2022.849363/fullagent-based modelCAR T-cellsimulationcell population dynamicsmodel-guided designemergent dynamics |
| spellingShingle | Alexis N. Prybutok Jessica S. Yu Jessica S. Yu Joshua N. Leonard Joshua N. Leonard Joshua N. Leonard Joshua N. Leonard Neda Bagheri Neda Bagheri Neda Bagheri Neda Bagheri Neda Bagheri Mapping CAR T-Cell Design Space Using Agent-Based Models Frontiers in Molecular Biosciences agent-based model CAR T-cell simulation cell population dynamics model-guided design emergent dynamics |
| title | Mapping CAR T-Cell Design Space Using Agent-Based Models |
| title_full | Mapping CAR T-Cell Design Space Using Agent-Based Models |
| title_fullStr | Mapping CAR T-Cell Design Space Using Agent-Based Models |
| title_full_unstemmed | Mapping CAR T-Cell Design Space Using Agent-Based Models |
| title_short | Mapping CAR T-Cell Design Space Using Agent-Based Models |
| title_sort | mapping car t cell design space using agent based models |
| topic | agent-based model CAR T-cell simulation cell population dynamics model-guided design emergent dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2022.849363/full |
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