Hadjigeorgiou Andreas G, Munn Lance L, Stylianopoulos Triantafyllos, Jain Rakesh K
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus.
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
bioRxiv. 2025 Aug 21:2025.08.20.671229. doi: 10.1101/2025.08.20.671229.
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.
异常血管限制了内源性T细胞以及过继转移的嵌合抗原受体（CAR）-T细胞在肿瘤微环境（TME）中的递送和功能。我们最近表明，使用抗血管内皮生长因子（VEGF）疗法进行血管正常化可以克服这些挑战，并改善小鼠胶质母细胞瘤模型中CAR-T疗法的疗效。在这里，我们建立了一个基于生理学的药代动力学模型，以模拟血管正常化后实体瘤中过继转移的CAR-T细胞和内源性免疫细胞的动态变化。与我们的数据相似，我们的模型模拟表明，血管正常化将TME从免疫抑制状态重编程为免疫支持状态，增强内源性CD8 T细胞和CAR-T细胞的浸润，增加M1巨噬细胞，并减少M2巨噬细胞和调节性T细胞，从而提高疗效。引人注目的是，血管正常化将控制肿瘤所需的输注CAR-T细胞数量减少了一个数量级。此外，在其增殖高峰期同步进行第二次CAR-T输注可使抗肿瘤功能最大化。此外，经过工程改造以分泌抗VEGF抗体的CAR-T细胞的疗效取决于CAR-T细胞诱导血管正常化的能力。此外，联合血管和基质正常化可以提高产生抗VEGF抗体的FAP-CAR-T细胞治疗诸如胰腺导管腺癌等促结缔组织增生性肿瘤的疗效。最后，该模型预测局部CAR-T递送可以在TME内维持高浓度，并诱导其他抗肿瘤免疫细胞的募集，从而改善治疗结果。我们的模型提供了一个通用框架，以优化给药策略、治疗顺序和递送途径，从而改善实体瘤的CAR-T疗法。
