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| Format: | Preprint |
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2024
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| Online Access: | https://arxiv.org/abs/2411.12123 |
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| _version_ | 1866910230226403328 |
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| author | Hawi, Georgio Kim, Peter S. Lee, Peter P. |
| author_facet | Hawi, Georgio Kim, Peter S. Lee, Peter P. |
| contents | Colorectal cancer (CRC) poses a major public health challenge due to its increasing prevalence, particularly among younger populations. Microsatellite instability-high (MSI-H) CRC and deficient mismatch repair (dMMR) CRC constitute 15% of all CRC and exhibit remarkable responsiveness to immunotherapy, especially with PD-1 inhibitors. Despite this, there is a significant need to optimise immunotherapeutic regimens to maximise clinical efficacy and patient quality of life. To address this, we employ a novel framework driven by delay integro-differential equations to model the interactions among cancer cells, immune cells, and immune checkpoints in locally advanced MSI-H/dMMR CRC (laMCRC). Several of these components are being modelled deterministically for the first time in cancer, paving the way for a deeper understanding of the complex underlying immune dynamics. We consider two compartments$\unicode{x2014}$the tumour site and the tumour-draining lymph node (TDLN)$\unicode{x2014}$taking into account phenomena such as DC migration, T cell proliferation, and CD8+ T cell exhaustion and reinvigoration. Parameter values and initial conditions are derived from experimental data, integrating various pharmacokinetic, bioanalytical, and radiographic studies, along with deconvolution of bulk RNA-sequencing data from the TCGA COADREAD and GSE26571 datasets. We finally optimised neoadjuvant treatment with pembrolizumab, a widely used PD-1 inhibitor, to balance efficacy, efficiency, and toxicity in laMCRC patients. We mechanistically analysed factors influencing treatment success and improved upon currently FDA-approved therapeutic regimens for metastatic MSI-H/dMMR CRC, demonstrating that a single medium-to-high dose of pembrolizumab may be sufficient for effective tumour eradication while being efficient, safe, and practical. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2411_12123 |
| institution | arXiv |
| publishDate | 2024 |
| record_format | arxiv |
| spellingShingle | Optimisation of neoadjuvant pembrolizumab therapy for locally advanced MSI-H/dMMR colorectal cancer using data-driven delay integro-differential equations Hawi, Georgio Kim, Peter S. Lee, Peter P. Cell Behavior Dynamical Systems Tissues and Organs Colorectal cancer (CRC) poses a major public health challenge due to its increasing prevalence, particularly among younger populations. Microsatellite instability-high (MSI-H) CRC and deficient mismatch repair (dMMR) CRC constitute 15% of all CRC and exhibit remarkable responsiveness to immunotherapy, especially with PD-1 inhibitors. Despite this, there is a significant need to optimise immunotherapeutic regimens to maximise clinical efficacy and patient quality of life. To address this, we employ a novel framework driven by delay integro-differential equations to model the interactions among cancer cells, immune cells, and immune checkpoints in locally advanced MSI-H/dMMR CRC (laMCRC). Several of these components are being modelled deterministically for the first time in cancer, paving the way for a deeper understanding of the complex underlying immune dynamics. We consider two compartments$\unicode{x2014}$the tumour site and the tumour-draining lymph node (TDLN)$\unicode{x2014}$taking into account phenomena such as DC migration, T cell proliferation, and CD8+ T cell exhaustion and reinvigoration. Parameter values and initial conditions are derived from experimental data, integrating various pharmacokinetic, bioanalytical, and radiographic studies, along with deconvolution of bulk RNA-sequencing data from the TCGA COADREAD and GSE26571 datasets. We finally optimised neoadjuvant treatment with pembrolizumab, a widely used PD-1 inhibitor, to balance efficacy, efficiency, and toxicity in laMCRC patients. We mechanistically analysed factors influencing treatment success and improved upon currently FDA-approved therapeutic regimens for metastatic MSI-H/dMMR CRC, demonstrating that a single medium-to-high dose of pembrolizumab may be sufficient for effective tumour eradication while being efficient, safe, and practical. |
| title | Optimisation of neoadjuvant pembrolizumab therapy for locally advanced MSI-H/dMMR colorectal cancer using data-driven delay integro-differential equations |
| topic | Cell Behavior Dynamical Systems Tissues and Organs |
| url | https://arxiv.org/abs/2411.12123 |