Research Spotlight: New Model Provides a Roadmap for Optimal CAR-T Cell Therapy in Solid Tumors

CAR-T cells are T cells that have been extracted from a patient, modified in a laboratory to recognize and target cancer cells then infused back into the patient. They have revolutionized the treatment of many blood cancers, but have not yet benefited patients with solid tumors, such as lung, breast, colorectal or brain tumors.

By developing a sophisticated mathematical model, we demonstrated that normalizing tumor blood vessels — which means transforming the abnormal, disorganized vasculature of a tumor into a more normal, structured and functional state — can improve the efficacy of CAR-T therapy and reduce the required therapeutic dose by about fivefold. 

Q: What central question were you investigating?

We set out to investigate how to make CAR-T cell therapy more effective in treating glioblastoma and other solid tumors by normalizing tumor blood vessels and surrounding tissue. Specifically, we explored different approaches to overcoming abnormalities in the tumor microenvironment that we know hinder the efficacy of CAR-T therapy, and whether these interventions might enhance therapeutic activity and reduce required dosing.

Our goal was to identify optimal delivery routes, dosing regimens, treatment protocols and combination strategies that could guide future experimental and clinical applications.

Q: What methods or approach did you use?

To address this, we developed a type of mathematical model called a PBPK model to simulate how CAR-T cells and endogenous immune cells (those we naturally produce) move and interact within the body. Using this modeling framework, we were able to test several therapeutic strategies to better understand how the tumor microenvironment can be modulated to improve CAR-T efficacy.

For example, we explored how variations in dosing strategies, timing and delivery routes impacted the immune cells’ ability to infiltrate the tumor and produce the desired response. We also studied the potential of CAR-T cells engineered to secrete anti-VEGF antibodies, which block a signal in the body to grow new blood vessels. Finally, we investigated synergistic approaches that combine the normalization of blood vessels with the normalization of dense tissue to overcome the characteristics of certain solid tumors.

To our knowledge, this is the first modeling platform that integrates tumor blood vessel and tissue normalization into a mechanistic CAR-T systems model for solid tumors. This in silico framework provides a versatile, low-cost tool to optimize protocols before advancing to preclinical or clinical studies.

Q: What did you find?

Our model successfully reproduced experimental data on tumor growth and immune infiltration, validating its ability to capture CAR-T and endogenous immune dynamics under different tumor microenvironment conditions. Overall, our results highlight how normalization strategies, combined with optimized dosing, timing and delivery, can substantially improve CAR-T cell therapy in glioblastoma and other solid tumors.

Q: What are the implications?

Our work has several important clinical implications for advancing CAR-T therapy in solid tumors. By demonstrating that normalizing tumor blood vessels can enhance CAR-T trafficking and significantly reduce the required therapeutic dose, our findings suggest a strategy to make treatment safer and more accessible. Lower doses could reduce manufacturing demands, lessen the risk of severe treatment-related toxicities and expand the availability of CAR-T therapy to more patients.

The model also highlights the critical role of timing and delivery strategy. Optimizing infusion schedules sustains antitumor responses while avoiding T cell exhaustion. In cancers that trigger the body to form dense, fibrous tissue around the tumor (such as pancreatic cancer), taking a combined approach to normalize both tumor blood vessels and surrounding tissue could provide more effective tumor shrinkage and broaden the therapeutic window.

For brain tumors such as glioblastoma, we found local delivery to be a particularly promising approach, offering equivalent tumor control with vastly fewer CAR-T cells, while preserving systemic T cell circulation and reducing off-target toxicity.

Together, these insights point toward safer, more effective and precision-guided CAR-T therapies for solid tumors, potentially opening new therapeutic avenues for hard-to-treat cancers like glioblastoma.

Q: What are the next steps?

The next steps will focus on systematically validating, refining and expanding our modeling framework to bring it closer to clinical application. In parallel, we will move toward tailoring model parameters to individual patients.

We also plan to expand the framework to other tumor types such as pancreatic cancer, certain breast subtypes, and sarcomas and metastatic lesions. Beyond CAR-T cells, we will incorporate additional therapies such as checkpoint inhibitors, chemotherapy and radiation to simulate rationally designed multi-modal regimens.

Finally, we envision translating this work into practical tools for clinicians. Building a user-friendly interface will allow oncologists to explore “what-if” scenarios in silico, and collaborations with clinical teams will help design early-phase trials guided by model-predicted schedules, dosing thresholds and delivery strategies.