Optimising Immunotherapy for Colorectal Cancer through Mathematical Modeling

Strategic Insights -

Research from the University of Sydney has used a novel framework driven by delay integro-differential equations to model the interactions among cancer cells, immune cells, and immune checkpoints in locally advanced microsatellite instability-high (MSI-H) and deficient mismatch repair (dMMR) colorectal cancer (CRC). This approach has enabled the optimisation of neoadjuvant treatment with pembrolizumab, a widely used PD-1 inhibitor, to balance efficacy, efficiency, and toxicity in laMCRC patients. The study demonstrated that a single medium-to-high dose of pembrolizumab may be sufficient for effective tumour eradication while being efficient, safe, and practical.

Key Takeaways:

  • Colorectal cancer (CRC) poses a significant public health challenge due to its increasing prevalence, particularly among younger populations, with MSI-H and dMMR CRC constituting 15% of all CRC and exhibiting remarkable responsiveness to immunotherapy.
  • The study employed 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.
  • Parameter values and initial conditions were derived from experimental data, integrating pharmacokinetic, bioanalytical, and radiographic studies, as well as deconvolution of bulk RNA-sequencing data from the TCGA COADREAD and GSE26571 datasets.
  • The research optimised neoadjuvant treatment with pembrolizumab to balance efficacy, efficiency, and toxicity in laMCRC patients.
  • The study demonstrated that a single medium-to-high dose of pembrolizumab may be sufficient for effective tumour eradication while being efficient, safe, and practical.
  • The research has improved upon currently FDA-approved therapeutic regimens for metastatic MSI-H/dMMR CRC.

Statistics:

  • 15% of all CRC are MSI-H or dMMR subtypes.
  • The study optimised neoadjuvant treatment with pembrolizumab, a widely used PD-1 inhibitor.
  • The research demonstrated that a single medium-to-high dose of pembrolizumab may be sufficient for effective tumour eradication.
  • The study has improved upon currently FDA-approved therapeutic regimens for metastatic MSI-H/dMMR CRC.

Sources:

  • NewsRx. Studies in the Area of Colon Cancer Reported from University of Sydney (Optimisation of neoadjuvant pembrolizumab therapy for locally advanced MSI-H/dMMR colorectal cancer using data-driven delay integro-differential equations). Cancer Weekly. August 26, 2025; p 892.
  • Journal of Theoretical Biology. Optimisation of neoadjuvant pembrolizumab therapy for locally advanced MSI-H/dMMR colorectal cancer using data-driven delay integro-differential equations. 2025;613:112231.