Ziopharm tests new approach to engineering CAR-Ts for solid tumors

Ziopharm CEO Laurence Cooper

One of the big challenges involved in engineering CAR-T cells to attack cancer revolves around its extension from B cell malignancies--where it's been remarkably successful--to solid tumors. A new mouse study from Ziopharm, one of the players in this field, suggests that leveraging a drug's affinity for EGFR, or other overexpressed proteins, may offer a route around toxicity issues that make solid tumors a hard target.

The CEO of Ziopharm, Laurence Cooper, started with the observation that the protein epithelial growth factor receptor (EGFR), is found clustered on the surface of cancer cells and in lower volumes on normal tissue. Using wild-type EGFR found in glioblastoma cells, investigators at MD Anderson in Texas created two different CAR-Ts, using the cetuximab antibody with a high affinity for EGFR and nimotuzumab with a low affinity for EGFR.

Trying it out on mice, they concluded that the high affinity cetuximab destroyed a large number of healthy cells as well as disease cells, while the low affinity nimotuzumab concentrated more around the cancer cells, leaving healthy tissue alone.

"The goal of the study was to make CAR-expressing T cells differentiate friend from foe," says Cooper, who was recruited from MD Anderson to take the helm at Ziopharm back in May. "We wanted to provide CAR T cells an improved opportunity of targeting a protein that is overexpressed on a cancer cell and spare normal cells that may also have the same protein, but at lower levels."

And what worked in EGFR can be applied to other overexpressed cancer proteins.

Early this year, Ziopharm and its ally Intrexon inked a $100 million CAR-T research pact with MD Anderson to come up with a new and better approach to devising the cancer therapies.

"We think this provides an advance in the field of CAR T-cell therapy because until now the focus in terms of T-cell activation was on the intracellular portion of the CAR design, which led to the development of second- and third-generation CARs with different abilities to signal T cells. Our study has shown that another possibility is to tweak the extracellular portion of the CAR that docks with the tumor by adjusting its affinity for the target protein," he added. "An important derivative of this study is that scientists can now tweak, or modulate, the affinity of a CAR T cell to meet the needs of a given tumor."

The study was published in Cancer Research, a journal of the American Association for Cancer Research.

- here's the release
- read the research article

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