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Development of novel PD-L1 and PD-L2 CAR-T cells for use against pediatric solid tumors

Shin C, Imamura M, Kasaha Y, et al. Chimeric PD-1 Receptor Redirects Primary T Cells Against Childhood Solid Tumors But Not to PD-1 Ligand-Positive CD80-Coexpressing Cells. Molecular Medicine Reports. 2025; (doi: 10.3892/mmr.2025.13608).

Programmed cell death 1 (PD-1) ligands may be part of the challenge in applying chimeric antigen receptor (CAR) T-cell therapy to solid tumors but, researchers suspect, they also could be part of the solution. Engineering CAR T cells to target PD-L1 and PD-L2, which are abundantly expressed in a number of pediatric solid tumors, reportedly has demonstrated potential. By promoting T-cell dysfunction, the antigens help tumors to dodge immune activity and continue to thrive. However, a study has found that CAR-T cells directed at PD-L1 and PD-L2 demonstrate robust cytotoxicity against solid pediatric tumors that express the immune checkpoint molecules. Investigators observed that killing activity intensified slightly when PD-1 CAR-T cells were used in tandem with another CAR targeting a separate antigen. In contrast, the effect was significantly weakened in PD-L1-positive cells that also expressed CD80, which discourages PD-1 CAR binding. According to the study authors, the most promising traits of PD-1 CAR-T cells are their broad utility in pediatric cancers with few or no target antigens and their ability to deflect tumor-driven immune evasion. Future research should look more closely at PD-1 CAR T cells administered with CD19, HER2, or another conventional CAR T cell.

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