T-Cell–Based Immune Therapy Treats EBV-LPD

One dangerous complication of a bone marrow transplant is that the Epstein-Barr virus (EBV), which is dormant in most people, will trigger EBV-associated lymphoproliferative disorder (EBV-LPD) in the transplant recipient. Leukemia patients who develop EBV-LPD have a terrible prognosis: Median survival is just 31 days.

Until now, there have been just two treatment options for these patients: rituximab (Rituxan; Genentech/Biogen), which often fails, or a second infusion of T cells, treated to target EBV, from the transplant donor. However, the process of expanding donor T cells in culture and stimulating them to respond to EBV proteins takes 61 days. Few patients live that long.

Now, researchers from Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY, have short-circuited the process by preparing and banking EBV-fighting T cells ahead of time. With 330 variants of these T cells, they say they can now match about 99% of patients. As soon as a match can be made, the specialized T cells, called Epstein-Barr virus–specific cytotoxic T lymphocytes (EBV-CTL), can be dispatched to the patient.

“T cells can be turned into an off-the-shelf reagent to treat this complication in patients after bone marrow transplantation,” said Suzanne L. Topalian, MD, director of the melanoma program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD. She moderated a press conference at which the results of two trials were presented, as part of the American Association for Cancer Research Annual Meeting 2015, held in Philadelphia, PA, April 18–22.

In the two clinical trials, more than 60% of patients had a complete response to the therapy. In the first, which began more than 5 years ago, 26 patients received three weekly doses of EBV-CTLs generated from their donor's cells and 13 received HLA-matched T cells from the MSKCC bank. Twenty-three patients experienced complete responses, 9 of whom have already survived at least 5 years. Although patients who received banked cells were more likely to need additional cycles of therapy, the percentage of respondents was nearly identical (62% for primary donor cells vs. 61% for banked cells).

In the second trial, nine of 18 patients who received matched EBV-CTLs from the bank had a complete response, all of whom continue to do well. Three others had a partial response and one had stable disease.

Toxicities were minimal, and most patients handled even extended treatments without serious complications, said Richard J. O'Reilly, MD, chief of the pediatric bone marrow transplant service at MSKCC, who led the research. In addition, there were no serious instances of acute or chronic graft-versus-host disease, he said.

Impressed with the results, the FDA granted Breakthrough Therapy designation to MSKCC on March 2 for the development of EBV-CTLs generated from the blood of third-party donors to treat patients with rituximab-refractory EBV-LPD. MSKCC is collaborating with Atara Biotherapeutics of South San Francisco, CA, on the therapy.

So far, only patients at MSKCC have been treated, but O'Reilly said he hopes that any doctor will soon be able to send their patients' HLA type to the bank and receive matched EBV-CTLs within a few days.

Patrick J. Hanley, PhD, an assistant professor at The George Washington University in Washington, DC, said he is excited about the MSKCC team's efforts to standardize EBV-LPD treatment. Right now, doctors must often scramble to fund treatment as they try to save their patients' lives, because insurance won't cover experimental treatments.

“Now it can become mainstream and a licensed [approach],” said Hanley, who was first author on a recent paper showing that naïve immune cells taken from cord blood can be stimulated to fight cytomegalovirus and other opportunistic viruses.

O'Reilly added that he'd like to study the banking approach to fight other viruses, such as adenovirus, and other instances of EBV, such as EBV-associated Hodgkin disease. “We're just starting to get at that,” he said.