Two infants with relapsed, refractory B-cell acute lymphoblastic leukemia went into complete remission after being treated with CD19-targeting CAR T cells derived from an unmatched donor. The study is the first to demonstrate that a universal form of CAR T-cell therapy can be safely utilized.

In a groundbreaking study, two infants with relapsed, refractory B-cell acute lymphoblastic leukemia (B-ALL) went into complete remission after being treated with CD19-targeting chimeric antigen receptor (CAR) T cells from an unmatched donor. Up to now, these genetically modified cells have had to be tailor-made for each individual patient. This is the first demonstration that a universal form of CAR T-cell therapy can be safely utilized (Sci Transl Med 2017;9:eaaj2013).

Collaborating with the French biotech Cellectis, researchers from University College London, UK, used a novel gene-editing enzyme, TALEN, to modify T cells from a healthy donor in two key ways. First, they deleted a region of the native T-cell receptor to minimize the risk of graft-versus-host disease. Next, they disrupted expression of CD52 to give the cells a survival advantage.

The altered cells, called UCART19, were then infused into an 11-month-old infant and a 16-month-old infant, both of whom had been treated with immunosuppressive chemotherapy. They achieved molecular remission—no evidence of disease within blood cells or bone marrow, as indicated by PCR—within 28 days, and then received allogeneic stem cell transplants. At the time this study was published, the two young patients had been disease-free for 12 months and 18 months, respectively.

“This new approach has the potential to open up CAR T-cell therapy to many more children,” says Marie Bleakley, MD, PhD, a pediatric oncologist and expert in hematopoietic stem cell transplantation at Fred Hutchinson Cancer Research Center in Seattle, WA. “It shows that it's possible to create an off-the-shelf product that is much less expensive and time-consuming to produce than customized therapies.”

Besides the need for individually tailored CAR T cells, there have been other roadblocks to making this therapy more widely available, including the logistic challenge of transporting patient cells to and from highly specialized manufacturing facilities. In addition, infants and heavily treated patients often do not have sufficient numbers of healthy T cells to even begin the manufacturing process. Being able to produce this immunotherapy in batches, using T cells from unmatched donors, would allow speedier treatment at far lower costs.

“If we had a bank of cells waiting, we could potentially treat patients within 1 or 2 weeks of them walking through the door,” says Kevin J. Curran, MD, a hematopoietic stem cell transplantation specialist and head of the pediatrics CAR T-cell therapy program at Memorial Sloan Kettering Cancer Center in New York, NY. However, he cautioned that these findings are only a first step toward realizing the promise of universal CAR T cells.

“This is an exciting start to showing that an off-the-shelf approach is possible, but it has only been tried in two patients,” he says. “We now need to ramp up production and test it in more people with hematological malignancies as well as solid tumors.”

In the UK, UCART19 is currently being evaluated in phase I trials for ALL and chronic lymphocytic leukemia. Meanwhile, in the United States, Cellectis has received the FDA's go-ahead to begin testing another product, UCART123, in patients with acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm. –Janet Colwell

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©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.