Two is Better Than One: T Cells That Target Two Tumor Surface Molecules Mitigate Tumor Escape in a Mouse Model of Glioblastoma

Style Magazine Newswire | 7/18/2016, 5:17 p.m.
A solid tumor comprises a heterogeneous population of cells that differ from each other on their type of surface molecules. ...
Baylor College of Medicine

HOUSTON – (July 18, 2016) – A solid tumor comprises a heterogeneous population of cells that differ from each other on their type of surface molecules. In an article published today in the Journal of Clinical Investigation, researchers from Baylor College of Medicine, Texas Children’s Cancer Center and the Center for Cell and Gene Therapy at Baylor, Texas Children’s Hospital and Houston Methodist Hospital show a new strategy, based on targeting specific surface molecules, that eliminates most of the cancer cells in a mouse model of glioblastoma, mitigates tumor escape, controls tumors better and improves animal survival.

“Tumors are a community of heterogeneous cells that use this heterogenicity to their advantage,” said senior author Dr. Nabil Ahmed, associate professor of pediatrics at Baylor and Texas Children’s Cancer Center.

The researchers wanted to understand what happens to tumors when a treatment targets a single surface molecule. First-author Dr. Meenakshi Hegde, assistant professor in pediatrics at Baylor, worked with glioblastoma tumor cells in the lab and in a mouse model of glioblastoma. She targeted a single surface molecule on the tumor cells with chimeric antigen receptor T cells, or CAR T cells. CAR T cells are T cells – a type of immune cells involved in defense against tumors – that have been programmed to recognize and kill tumor cells carrying one specific antigen on the surface of cancer cells through an artificial molecule expressed on their surface, the CAR.

Hegde asked, when we target a single antigen on tumor cells with CAR T cells, what happens to the tumor? CAR T cells eliminated the cells that had the target on their surface, the one they had been programmed to recognize, leaving behind the cells without the target. When Hegde carried out this experiment in the mouse model, she observed that, although part of the tumor had been eliminated by CAR T cells, in time, the tumor relapsed. The relapsed tumor cells were not carrying the target the CAR T cells recognized but instead carried other surface molecules.

These results taught the researchers that “targeting one type of surface molecule on a tumor kills only the cells that carry that antigen. The cells that do not carry the surface molecule are spared and can continue growing. They become the cells that cause relapse,” said Ahmed. The researchers then tested what would happen if they used CAR T cells to target two different tumor surface molecules, simultaneously. They found that “if we target more than one antigen, we have a better chance of mitigating tumor escape,” said Ahmed.

The antigens the researchers selected, called HER2 and IL13Rα2, are good candidates for tumor therapy because they are expressed on the surface of most glioblastoma cells, but expressed in very low quantities on normal tissues of the body. This is important to minimize CAR T cells targeting and killing normal cells.

The researchers determined what would happen if the CARs on T cells that bound to HER2 and IL13Rα2 were single bivalent molecules; that is, one molecule that could bind both antigens simultaneously. When T cells recognized HER2 and IL13Rα2 simultaneously through a single bivalent CAR molecule, the anti-tumor “activity was much higher than when separate CAR molecules were used,” said Ahmed.