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: the tumour site and the tumour-draining lymph node, incorporating phenomena such as dendritic cell (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.