CELL INTELLIGENCE · 肿瘤细胞治疗研究

Abnormal blood vessels limit the delivery and function of endogenous T cells as well as adoptively transferred Chimeric Antigen Receptor (CAR)-T cells in the tumor microenvironment (TME).

We recently showed that vascular normalization using anti-VEGF therapy can overcome these challenges and improve the outcome of CAR-T therapy in glioblastoma models in mice.

Here, we developed a physiologically based pharmacokinetic model to simulate the dynamics of both adoptively transferred CAR-T cells and endogenous immune cells in solid tumors following vascular normalization.

Similar to our data, our model simulations show that vascular normalization reprograms the TME from immunosuppressive to immunosupportive-enhancing infiltration of endogenous CD8 + T cells and CAR-T cells, increasing M1 macrophages, and reducing M2 macrophages and regulatory T cells-thereby improving efficacy. Strikingly, vascular normalization reduces the number of infused CAR-T cells needed for tumor control by an order of magnitude.

Moreover, synchronizing a second CAR-T infusion at their peak proliferative phase maximizes antitumor function.

Furthermore, the efficacy of CAR-T cells engineered to secrete anti-VEGF antibody depends on the ability of CAR-T cells to induce vascular normalization.

Additionally, combining vascular and stromal normalization can improve the efficacy of anti-VEGF antibody-producing FAP-CAR-T cells for the treatment of desmoplastic tumors such as pancreatic ductal adenocarcinoma.

Finally, the model predicts that local CAR-T delivery can sustain high concentrations within the TME and induce recruitment of other antitumor immune cells, improving outcomes.

Our model provides a versatile framework to optimize dosing strategies, treatment sequencing, and delivery routes for improving CAR-T therapies for solid tumors.