Optimisation of neoadjuvant pembrolizumab therapy for locally advanced MSI-H/dMMR colorectal cancer using data-driven delay integro-differential equations

Abstract

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.

102 pages in total with 63 pages for the main body and 39 pages for the supporting information. Minor edits made. Published in the Journal of Theoretical Biology