Physiologically-based pharmacokinetic model for CAR-T cells delivery and efficacy in solid tumors

Abstract

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. Significance Statement Preclinical studies and early clinical trials of CAR-T therapy show encouraging responses in glioblastoma, diffuse midline gliomas, and neuroblastoma, yet substantial obstacles remain for effective CAR-T therapy for solid tumors. Building on our discovery that judicious VEGF blockade normalizes tumor vessels and enhances CD8T-cell infiltration, we developed a mathematical model to optimize CAR-T therapy for solid tumors. Simulations predict that vascular normalization can render the TME immunosupportive and decrease CAR-T doses tenfold. In desmoplastic tumors, FAP-CAR-T efficacy is improved by combining anti-VEGF and stromal normalizing agents. Optimal scheduling and direct intratumoral delivery can mitigate T-cell exhaustion and improve tumor control further. Thus, our model serves as a strategic roadmap for optimal CAR-T deployment in solid tumors.