UCLA Scientists Engineer Off-the-Shelf T Cells That Track Down Hiding Tumors

UCLA scientists have engineered off-the-shelf T cells from cord blood stem cells that can hunt solid tumors even when cancer cells hide their target. The approach, published in Cell Reports Medicine, tackles two problems limiting a cancer treatment called T cell receptor (TCR) therapy.

TCR therapy genetically modifies a patient's immune cells, called T cells, to recognize and attack cancer precisely. Unlike CAR T-cell therapy, TCR therapy can also detect protein fragments carried to a cancer cell's surface from inside it, giving it more targets — important for solid tumors. Current TCR treatments are usually made from a patient's own T cells, taking weeks and costing well into six figures.

Donor T cells could let treatments be made in advance and stored, but can cause graft-versus-host disease, in which transplanted immune cells attack healthy tissue. The UCLA team, led by co-senior author Lili Yang, addressed both problems by starting with cord blood stem cells instead of mature donor T cells. They inserted a gene for a receptor recognizing NY-ESO-1, a protein found in many solid tumors, then guided the modified stem cells into T cells called AlloESO-T cells in the lab.

Adding the receptor at the stem cell stage stops the cells from making their own natural T cell receptors, so nearly all resulting cells target the same protein, said co-first author Yichen (John) Zhu. The AlloESO-T cells also carry natural killer cell receptors that detect stress signals tumor cells display, giving a backup way to kill tumor cells hiding NY-ESO-1 (antigen escape). Lab tests on human melanoma, ovarian and prostate cancer cells confirmed this backup pathway worked.

In mouse models, one dose of AlloESO-T cells produced lasting tumor control and prolonged survival in both ovarian cancer and melanoma, without dangerous side effects. Mice given T cells engineered from mature donor T cells showed only partial or temporary tumor control, and in the ovarian cancer test also developed graft-versus-host disease.