Carbonic Anhydrase IX Suppression Shifts Partial Response to Checkpoint Inhibitors into Complete Tumor Eradication: Model-Based Investigation

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of solid malignancies, including non-small-cell lung cancer. However, immunotherapy resistance constitutes a significant challenge. To investigate carbonic anhydrase IX (CAIX) as a driver of resistance, we built a differential equation model of tumor–immune interactions. The model considers treatment with the small molecule CAIX inhibitor SLC-0111 in combination with ICIs. Numerical simulations showed that, given an efficient immune response, CAIX KO tumors tended toward tumor elimination in contrast to their CAIX-expressing counterparts, which stabilized close to the positive equilibrium. Importantly, we demonstrated that short-term combination therapy with a CAIX inhibitor and immunotherapy could shift the asymptotic behavior of the original model from stable disease to tumor eradication. Finally, we calibrated the model with data from murine experiments on CAIX suppression and combination therapy with anti-PD-1 and anti-CTLA-4. Concluding, we have developed a model that reproduces experimental findings and enables the investigation of combination therapies. Our model suggests that transient CAIX inhibition may induce tumor regression, given a sufficient immune infiltrate in the tumor, which can be boosted with ICIs.

Co-vulnerabilities of inhibiting carbonic anhydrase IX in ferroptosis-mediated tumor cell death

“…When used to evaluate the role of CAIX expression on the efficacy of immune checkpoint inhibitors (ICI), the model showed that CAIX expression inhibits the immune response and that suppressing CAIX expression improves response to immune checkpoint blockade ( Grajek et al, 2023 ). Computational modeling has also demonstrated that combination therapy using SLC-111 and ICI moves the incomplete response to ICI to tumour eradication ( Grajek and Poleszczuk, 2023 ). These studies highlight the ability of in silico studies to recapitulate experimental findings and suggest that they may offer an additional technological link between pre-clinical studies and clinical applications.…”