Optimizing infusion methods to enhance the efficacy of CAR-T cell therapy for solid tumors

Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable efficacy against hematological malignancies, but its application in solid tumors remains challenging, partly due to inefficient tumor trafficking. While intravenous (i.v.) infusion is the standard administration route, its effectiveness in solid tumors may be limited. This study evaluated alternative delivery strategies-intraperitoneal (i.p.) and peritumoral (p.t.) injection-in comparison to i.v. administration in solid tumor models. CAR-T cell persistence, tumor infiltration, exhaustion-associated receptors, and in vivo trafficking dynamics were assessed using flow cytometry, PET-CT imaging with ⁸⁹Zr-oxine-labeled CAR-T cells, and combination therapy with the anti-angiogenic agent anlotinib. I.p. infusion achieved superior antitumor efficacy, accompanied by enhanced CAR-T cell persistence in circulation and tumor tissue, and reduced expression of exhaustion-associated receptors on CAR-T cells. PET-CT tracking revealed that i.p. infusion produced early tumor-associated radioactivity comparable to that of i.v. infusion within 48 h, whereas endpoint flow cytometry showed greater tumor accumulation after i.p. and p.t. delivery than after i.v. delivery. Furthermore, combining i.p.-delivered CAR-T cells with anlotinib enhanced tumor control without impairing CAR-T cell infiltration, despite reduced vascular density. Our findings propose i.p. infusion as an optimized delivery route for CAR-T therapy in solid tumors and support its combination with anti-angiogenic treatment to improve outcomes.