A new “off-the-shelf” treatment promises to induce remission in rituximab (Rituxan)-refractory Epstein-Barr virus (EBV)-associated lymphoproliferative disorder, a potentially fatal complication of hematopoietic stem cell transplantation. Historically, this complication has been difficult to treat because the most effective treatment known to induce remission was to administer donor-derived EBV-immune T cells, which took 60 days or more to generate.
Study Background
“We wanted to develop an approach that can be delivered more rapidly,” said Richard J. O’Reilly, MD, Chair of the Department of Pediatrics at Memorial Sloan Kettering Cancer Center, New York. The novel approach that he and his colleagues studied is called EBV-specific cytotoxic T-lymphocyte therapy. As senior author of their investigation, Dr. O’Reilly spoke about the strategy at a press conference during the 2015 Annual Meeting of the American Association for Cancer Research (AACR).1 Susan E. Prockop, MD, also a pediatric oncologist at Memorial Sloan Kettering, presented the study results at the AACR meeting.
EBV reactivation often occurs in patients who undergo allogeneic bone marrow transplant. Some of these patients—ranging from 1% to 7%, depending on the type of transplant—will develop EBV-associated lymphoproliferative disorder.
“This is an extremely aggressive complication, and without therapy, patients die within 31 days,” Dr. O’Reilly said.
EBV-associated lymphoproliferative disorder in hematopoietic stem cell transplant recipients is most often diffuse large B-cell lymphoma; it is monomorphic or polyclonal, CD20-positive, and of donor origin. Patients can present with fever, exudative pharyngitis, abdominal pain, mental status changes, and disseminated intravascular coagulation. Common sites of involvement include Waldeyer’s ring, adenopathy above and below the diaphragm, intestine, liver/spleen, central nervous system, and lung.
At Memorial Sloan Kettering, the researchers developed a bank of virus-specific T cells from 330 donors. The T cells were expanded in culture and stimulated to respond to multiple proteins from the EBV. “These T cells are usable off the shelf and can be given to patients within 24 hours,” Dr. O’Reilly said.
To assess the usefulness of these banked cells, they evaluated the human leukocyte antigen (HLA) typing of 200 consecutive unrelated transplant and 100 cord blood transplant recipients and also fielded 175 requests from physicians for patients with EBV-associated malignancies, and were able to identify an EBV-specific cytotoxic T-lymphocyte line from the bank that was matched at two HLA alleles and appropriately HLA-restricted for 98.6% of these patients.
“The bank allows selection of partially HLA-matched EBV-specific [cytotoxic T lymphocytes] matched for two or more HLA alleles and that are HLA-restricted by an HLA allele expressed by the patient’s tumor for more than 98% of patients who do not respond to initial management,” Dr. O’Reilly said.
Key Data
At the AACR press conference, Dr. O’Reilly reported on 26 patients who developed EBV-associated lymphoproliferative disorder and received EBV-specific cytotoxic T lymphocytes from the original donor as well as two cohorts with a total of 31 patients who developed rituximab-refractory EBV-associated lymphoproliferative disorder and were treated with EBV-specific cytotoxic T lymphocytes from a third party. Patients received one course of three weekly infusions and were monitored for response. Those in complete remission at 3 weeks did not get any more treatment, whereas those in partial remission got additional doses.
Response rates were as follows: for those treated with donor-derived EBV-specific cytotoxic T lymphocytes, 62% achieved a complete or partial response. In the third-party group (ie, rituximab-refractory patients), 64% achieved a complete or partial response. All responses were comparable whether donor or third-party EBV-specific cytotoxic T lymphocytes were used, and responses were durable.
“We see responses by the second or third course of T cells, whether donor-derived or from a third party. You see complete resolution of disease,” he stated.
Long-term disease-free survival was 50% at 12 months for the 12 patients who received third-party EBV-specific cytotoxic T lymphocytes and 71.8% at 12 months for the second cohort.
T-Cell Pools
Currently, patients are referred to Memorial Sloan Kettering to receive cell therapy. However, in the future, physicians will be able to send the HLA pathology of patients who develop EBV- associated lymphoproliferative disorder to Memorial Sloan Kettering, and get appropriately EBV-selected, EBV-specific cytotoxic T lymphocytes back by return mail, he noted.
“There is the potential to develop banks of T cells to treat other disorders. My quest is to identify peptide antigens that distinguish these disorders and develop pools of antigen-specific T cells to be used for these diseases.” he stated.
The EBV-specific cytotoxic T-lymphocyte strategy has been assigned Breakthrough Therapy status by the U.S. Food and Drug Administration. ■
Disclosure: Dr. O’Reilly reported no potential conflicts of interest.
Reference
1. Prockop S, et al: 2015 AACR Annual Meeting. Abstract 8841. Presented April 19, 2015.
