New mathematical model tracks how tumor environment impacts cancer therapies

Researchers from Mass General Brigham and the University of Cyprus have developed a sophisticated mathematical model to better understand how the tumor microenvironment affects the delivery and effectiveness of a new type of cancer therapy called an immunomodulatory antibody-drug conjugate (IM-ADC).

The model, which was developed by a team led by Rakesh Jain, PhD, of the Department of Radiation Oncology at Mass General Brigham, incorporates key features of the tumor microenvironment, including abnormal blood vessels, elevated interstitial fluid pressure, immune cell activity, drug transport and tumor-draining lymph nodes.

The researchers used the model to assess HE-S2, an experimental IM-ADC therapy that combines an anti-PD-L1 antibody with an immune-stimulating payload called D18.

By fitting the model to published mouse studies, the researchers were able to reproduce observed tumor responses and explore biological processes that cannot easily be measured experimentally.

Through this modeling work, the team found that HE-S2 was more effective as a treatment than either of its individual components alone.

The model also suggests the presence of a positive feedback loop: as the therapy decreases the size of the tumor, the interstitial fluid pressure decreases, which in turn improves drug delivery and further enhances treatment effectiveness. This normalization process can reduce vascular permeability if taken too far, however, as ADCs are large molecule therapeutics that need pores that are at least 40 nanometers in size to reach their target.

The results support strategies aimed at "normalizing" the tumor microenvironment before ADC treatment, such as improving blood vessel function while preserving sufficient vascular permeability to allow large antibody-based therapies to penetrate tumors.