MPZL1-Targeted CAR-T Cells Regress Solid Tumors After Single Dose in Mouse Models

Researchers at Heidelberg University Hospital screened genomic data and 2,200 tumor samples to identify MPZL1, a surface protein overexpressed in liver, breast, lung, pancreatic, and glioblastoma cells while remaining low in healthy tissue. They engineered CAR-T cells against the extracellular domain and tested them in vitro against patient-derived lines and in vivo in xenograft models. Tumor cells lacking MPZL1 were largely spared, confirming on-target activity.

The approach departs from conventional searches for driver mutations by focusing on chromosomal amplifications that place accessible surface proteins on cancer cells. In the mouse experiments, a single CAR-T infusion led to infiltration and activation within MPZL1-positive tumors, with reduced activity in normal tissues. This addresses a key barrier for solid-tumor CAR-T therapies that have succeeded mainly in hematologic malignancies.

Limitations include the inability of the human-specific CAR to recognize murine MPZL1, restricting off-tumor toxicity assessment, and the absence of large-animal safety data. Next steps require non-human primate studies to evaluate systemic effects before any first-in-human trial can be proposed.

Regulatory and manufacturing considerations for scaling this target will also need clarification, as will durability of responses beyond the short-term mouse observations.