The figure that matters: 3.5%. That is the non-relapse mortality Stanford’s Robert Negrin, MD, cited for patients who received Orca-T in a phase 3 trial, against the 10 to 15% he says typically die of complications after a bone marrow transplant. “That, to me, is perhaps the most important finding,” he said. The FDA has since approved the therapy, the first regulatory T cell treatment cleared for clinical use.
The problem it targets
A stem cell transplant can cure aggressive blood cancers, but it carries a built-in hazard. Patients first get chemotherapy or radiation to clear out their old immune cells, then receive donor cells that rebuild the immune system and hunt remaining cancer. Sometimes that new system turns on the patient’s organs. This is graft-versus-host disease, or GVHD, and it can be life-threatening. Doctors usually hold it back with heavy immunosuppressive drugs, which leave patients weak and open to infection and organ damage.
A firefly gene and a timing clue
Negrin worked with Chris Contag, PhD, to track transplanted T cells by inserting a gene from the North American firefly. The cells lit up. In animal models, donor T cells multiplied in the lymph nodes and spleen within a couple of days, yet symptoms in skin and gut did not show until weeks later. By then, Negrin said, the cells “just keep going and going and going” and the damage is hard to treat.
That pushed the team toward regulatory T cells, or Tregs, which restrain other T cells. Work by the late Sam Strober, MD, helped lay the groundwork. A conventional graft is a simultaneous mix of stem and immune cells. Negrin’s group instead fixed a Treg-to-T cell ratio and infused the types in sequence, with Tregs going in first. The animals avoided GVHD, kept their anti-tumor response and recovered immune function better.
From lab to approval
Scaling this up meant partnering with Orca Biosystems, whose platform sorts cell types to build the graft. Tregs go in with the healthy stem cells, and the T cells follow two days later. The multicenter Precision-T trial tested Orca-T (TREGZI) in adults with acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome. Everett Meyer, MD, PhD, was the lead author. Patients on Orca-T had significantly lower rates of acute and chronic GVHD than those on standard transplants. They also needed less aggressive immunosuppression afterward, spent fewer days in hospital and had fewer severe infections. “They just go through it a lot more easily,” Negrin said.
The team has also combined Orca-T with donor-derived CAR-T cells for high-risk patients with acute lymphoblastic leukemia, in a study led by Lori Muffly, MD, and Melody Smith, MD. “It’s not the end,” Negrin said of the approval, “it never is.”
