Abstract

On-target, off-tumor toxicity presents a significant challenge in chimeric antigen receptor (CAR) T therapy for solid tumors. Traditional approaches to managing adverse reactions, such as suppressing in vivo CAR-T cell activity, risk impairing their antitumor efficacy, often resulting in treatment failure. Intravenously infused CAR-T cells initially traffic to the lungs, where they are activated by tumor-associated antigens (TAAs) expressed on pulmonary tissues, leading to acute lung injury. To address this, this study developed a strategy involving leukocyte function-associated antigen 1 (LFA-1) neutralization at the time of infusion. This approach modulates CAR-T cell pharmacokinetics to enhance efficacy while minimizing toxicity. Post-infusion, CAR-T cells preferentially sequester and activate in the lung, secreting tumor necrosis factor α (TNF-α), which upregulates intercellular adhesion molecule 1 (ICAM-1) expression on pulmonary endothelial cells. This triggers an "activation-adhesion" feedback loop via the LFA-1/ICAM-1 pathway, exacerbating lung injury. Neutralization of LFA-1 during infusion significantly reduces CAR-T cell adhesion to pulmonary endothelium, disrupts this feedback loop, and mitigates acute lung injury. By accelerating the pharmacokinetic progression of CAR-T cells beyond the lung, this strategy not only alleviates the acute toxicity associated with high-dose regimens but also enhances the antitumor efficacy of low-dose CAR-T cells, thus expanding the therapeutic window.