Although chimeric antigen-receptor (CAR) T cell therapies are now being put to the test in the treatment of glioblastoma, neuroblastoma and, most remarkably, the swiftly lethal pediatric cancers known as diffuse midline gliomas, the strategy has proven decidedly less than effective for the treatment of most solid tumors. This is in large measure because CAR-T cells face the same challenges as ordinary anti-tumor T cells: they have trouble infiltrating the tumor and then are swiftly pushed into exhaustion or otherwise disabled by the harsh conditions they find in its microenvironment. The abnormal and dysfunctional blood vessels that feed tumors play no small part in this and several studies spearheaded by Ludwig Harvard’s Rakesh Jain have shown that normalizing these vessels using anti-angiogenic drugs, i.e. VEGF inhibitors, can restore the efficacy of both chemo and immunotherapy. In a November paper published in PNAS, researchers led by Rakesh reported a mathematical model for the optimization of CAR-T therapy against solid tumors. Their simulations show that vascular normalization with VEGF-blockade can lift immunosuppression considerably and reduce—by roughly fivefold—the dosage of CAR-T cells required to elicit a therapeutic effect. Their model, notably, also captures the benefits of optimal scheduling of the therapy and suggests that direct delivery of CAR-T cells to tumors could mitigate T cell exhaustion and improve outcomes.
Physiologically based pharmacokinetic model for CAR-T cell delivery and efficacy in solid tumors
PNAS, 2025 November 11