Cord blood inspires an alternative to CAR-T for treating blood cancers

As Novartis edges closer to FDA approval for tisagenlecleucel-T, its engineered immune-cell therapy for leukemia, scientists continue to search for ways to improve upon this new mode of immuno-oncology treatments. At the University of Texas M.D. Anderson Cancer Center, one team of researchers is turning to umbilical cord blood for inspiration.

The team has shown that certain cells called natural killer (NK) cells that are derived from cord blood can be genetically modified so they hunt down and kill leukemia and lymphoma, according to a press release. The scientists also figured out how to embed a “suicide gene” that shuts the cells down if they start to trigger cytokine release syndrome—a dangerous inflammatory response that has raised concerns during CAR-T clinical trials conducted by Novartis and its rivals.

Novartis’ tisagenlecleucel-T, first developed by scientists at the University of Pennsylvania, is made by taking blood from cancer patients, separating out T cells and inserting in them a chimeric antigen receptor (CAR) that targets CD19, which is an antigen that’s expressed on some blood cancers. The M.D. Anderson approach, by contrast, involves taking donated cord blood, separating out NK cells, and inserting a CD19-targeting CAR into them.

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But the M.D. Anderson approach did present one big challenge: NK cells don’t persist in the body for more than two or three weeks, limiting their potential utility as cancer treatments. So the researchers also equipped them with interleukin-15, a protein designed to help them stick around in the body for many months. In mouse models of lymphoma and chronic lymphocytic leukemia (CLL), the therapy extended survival beyond that of animals given NK cells alone, according to the release. The research was published in the journal Leukemia.

There are several advantages to using NK cells from umbilical cord blood, the M.D. Anderson researchers believe. In experiments, they found that engineered NK cells taken from healthy cord blood were more efficient at killing CLL cells than were NK cells that were taken from patients' blood and then engineered. What’s more, cord-blood-derived NK cells don’t have to be matched to patients. Past trials of the cells in patients have shown that they don’t cause graft vs. host disease—a dangerous consequence of unmatched T cells, which can attack normal tissues.

That means NK cells from cord blood could be manufactured and sold off-the-shelf, like a traditional pharmaceutical product, said Katy Rezvani, M.D., Ph.D., professor of stem cell transplantation and cellular therapy at M.D. Anderson, in the release. "CAR NK cells are scalable in a way that CAR T cells are not," she said.

The scalability of CAR-T treatments has, in fact, been one of the major challenges facing Novartis and its two biggest rivals in the space, Kite and Juno. All three companies have been working on shortening the turnaround time for producing their treatments. In June, Novartis committed to a 22-day manufacturing process. It won’t come cheap: Novartis has estimated that the cost of CAR-T treatments will rival the $800,000 cost of stem cell transplants.

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But patient safety was even more of a concern when an FDA advisory committee discussed tisagenlecleucel-T on July 12. In a phase 2 trial, 82% of patients had complete remissions, but 48% experienced cytokine release syndrome.

The M.D. Anderson scientists hope their engineered NK cells will sidestep that complication, too. So they incorporated the suicide gene, called iC9, into their experimental engineered cells. In mouse studies, they showed that iC9 responds to toxic inflammation by reducing the volume of engineered NK cells.

M.D. Anderson opened a phase 1/2 clinical trial of its NK cells in June. It will be testing the therapy in patients with CLL, acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma.