Big Ideas

Fatih Uckun, M.D., Ph. D.

Fatih Uckun, M.D., Ph.D., was awarded a 2011 V Foundation Translational Grant to fund immunotherapy research aimed at improving treatments for leukemia patients. The promising results indicate his laboratory successes could very well become weapons against not only leukemia, but also difficult-to-treat cancers.

B-lineage acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and the second most common form of acute leukemia in adults. Patients with this diagnosis typically respond well to chemotherapy. However, when the patient relapses, treatment becomes much more difficult. Positive results are harder to obtain. Uckun enthusiastically took on the challenge of changing that.

Uckun and his team genetically engineered proteins in our body to kill leukemia cells. We already possess a very small protein in our tissues known as sTRAIL. It can bind to death receptors on tumor cells and then kill them. But it has limitations: it is short-lived in circulation; the bind is often broken quickly; and it can be tricked by decoy death receptors. In short, it’s not the solution. But it has provided the spring board for Uckun’s research.

Using a larger protein – designated CD19-ligand or CD19L – directed against a target found on leukemia cells, his team has created a way to overcome the sTRAIL limitations. Because CD19L is larger, it stays in circulation a long time, which gives it time to bind to leukemia cells. The bind is strong, which allows a more sustained death signal to be relayed to the cancer cell.

The question became: how could you leverage these features of CD19L to make a much better use of the weapon (sTRAIL) and help it deliver the death signal more effectively? Uckun and his team genetically engineered a so-called fusion protein made up of CD19L and sTRAIL linked to each other with a flexible connection. When the CD19L portion of this fusion protein binds to leukemia cells, it serves like a superglue and allows the sTRAIL portion to tightly bind to the adjacent death receptors and deliver a fatal blow to the leukemia cell.

When viewed in test tubes and in mice, this fusion protein had a very promising record in cancer elimination.

“For many years, we have been hoping to develop a technological platform that would help destroy chemotherapy-resistant cancer cells”, said Uckun. “The potency of this particular new medicine candidate against leukemia cells provides the proof-of-principle that similar fusion proteins of sTRAIL could be prepared against other difficult-to-treat types of cancer as well,” he said.

The next step is collaboration between the best minds in the field from around the world. These researchers, once competitors, have agreed to collaborate with Uckun’s team on lab results.

“We’d align strengths to create a team dedicated to using this platform to eradicate therapy-resistant forms of cancer. It’s been and will continue to be a dedicated team effort that we hope will one day help patients,” he said.