TCR Gene Therapy Improves AML Prognosis

Treatment with T cells engineered to express a receptor for Wilms tumor antigen 1 (WT1) helps prevent relapse in patients with acute myeloid leukemia (AML) who have received an allogeneic stem-cell transplant.

The finding, from a 12-person trial of JTCR016 (Juno/Celgene), highlights the potential for T-cell receptor (TCR) gene therapy to improve outcomes in AML—a disease for which chimeric antigen receptor–modified T cells have had little clinical impact, in part owing to the lack of surface markers unique to leukemic blast cells (Nat Med 2019;25:1064–72).

“The study is really small, but it's very promising,” says Marcel van den Brink, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the research. “Our field is desperate for meaningful strategies to overcome a relapse, so a therapy like this is incredibly important—and can lead to real progress.”

Researchers from the Fred Hutchinson Cancer Research Center in Seattle, WA, developed the technology behind JTCR016. The bespoke therapy involves transducing CD8⁺ T cells taken from a transplant donor for each recipient with a TCR that recognizes a piece of WT1 presented on the cell surface by MHC molecules.

The substrate cells used to insert the WT1-specific TCR were selected for specificity to Epstein–Barr virus (EBV), as most cells recognizing EBV have central memory characteristics and are predicted to persist. EBV-specific T cells are also less prone to cause graft-versus-host disease (GVHD) than other immune cells, notes Patrick Hanley, PhD, of Children's National Medical Center in Washington, DC, and using them “as the vehicle to deliver the TCR is really creative.”

WT1 was chosen as a target because it is overexpressed in AML and other types of cancer. The TCR used in the therapy interacts with HLA-peptide complexes corresponding to the HLA-A*0201 allele present in about half of people of European ancestry.

Clinicians administered the TCR-bearing T cells within a few months of each patient's stem-cell transplant and shortly after tests showed no evidence of residual disease. Infusions were well tolerated, with no toxicity to tissues expressing normal levels of WT1 and no obviously elevated risk for GVHD.

After a median of 44 months, none of the trial participants had relapsed. Based on historical controls, about half would be expected to do so had they not received the TCR therapy.

The high levels of engraftment, persistence of the engineered T cells, and prolonged relapse-free survival point to a “very strong signal” of efficacy, says Aude Chapuis, MD, a co–first author of the study. “If I was a transplant patient,” she adds, “you bet I'd want to receive those cells”—at least before a relapse.

As Chapuis reported in July at the American Association for Cancer Research's Immune Cell Therapies for Cancer meeting in San Francisco, CA, the TCR-redirected T cells do not work as well against relapsed AML among patients with detectable disease.

Investigating the causes of failure in this unpublished work, Chapuis and her colleagues found ways to improve the therapy. They now hope to develop a product that engages helper CD4⁺ T cells alongside CD8⁺ T cells. Plus, because active leukemic cells had evolved to stop producing the piece of WT1 targeted by JTCR016, they are exploring whether targeting a different section generates better results. “We hope our 2.0 version will be a lot better,” Chapuis says. –Elie Dolgin

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