'Off-the-shelf' virus-specific T-cells fight viral infections in stem cell transplant patients
Viral infections present deadly threats to patients who have received donor blood, marrow and cord stem cells transplants and are immune deficient while their transplants begin to work. When drugs fail, T-cells specially engineered to target the viruses could help, but generating those when needed presents a major barrier.
In a new study that appears online in the journal Blood, researchers led by those at Baylor College of Medicine found that previously banked third party T-cells that specifically targeted three viruses that threaten recipients of such stem cell transplants offer a potent remedy for patients for whom antiviral drugs are not working.
In their study, the BCM researchers generated a bank of 32 cell lines specific for three viruses - Epstein-Barr, cytomegalovirus and adenovirus. Each was characterized to identify which viruses it could "see" or recognize so the investigators could identify the most suitable line for each patient. They used cells from 18 of these lines to treat 50 patients from eight centers across the country that had undergone a stem cell transplant and were suffering from a severe viral infection that had not responded to conventional treatment. Commonly, patients who undergo these stem cell transplants are immune suppressed after the procedure and before the transplanted cells repopulate their immune systems.
Six weeks after the cell infusion, 74 percent of those receiving the treatment had overcome the infection, either partially or completely and only four patients later had had a recurrence of the virus or progression of their diseases. This treatment was safe, with only two subjects developing new graft versus host disease in which the grafted T-cells attack the patients' normal cells, but this was mild in both cases and resolved rapidly. The numbers of virus-specific T-cells in their circulation increased after the infusion of the banked cells.
"What’s remarkable about these patients is that they had failed treatment with conventional antiviral therapies and subsequently responded to the T-cells," said Dr. Ann M. Leen, assistant professor of pediatrics - hematology/ oncology at BCM and a member of the Center for Cell and Gene Therapy at BCM, Texas Children's Hospital and The Methodist Hospital. "Many transplant centers do not have facilities to manufacture T-cell lines to treat viral infections. However, our bank of lines, which can be shipped all over the country, let us provide this new treatment more broadly that was previously possible."
"The standard way of making these cells takes three to four months," said Dr. Helen Heslop, professor of medicine - hematology/oncology at BCM, director of the Stem Cell Transplant program at The Methodist Hospital and also a member of the Center for Cell and Gene Therapy. "Moreover, we cannot make donor cells for a patient when the donor has never been exposed to the virus."
This method using the banked cells already shortens the wait time and a new method that Leen is developing could shorten the time to prepare the cells to no more than 10 days, said Heslop. She is also exploring the possibility of using the treatment in others patients who have an immune deficiency that could make them prone to life-threatening infections from these viruses.
Others who took part in this work include Drs. Catherine M Bollard; Adrian P Gee; Malcolm K Brenner; Cliona M Rooney and Bambi J Grilley, all of BCM; Adam M. Mendizabal of EMMES Corporation in Rockville, Maryland; Drs. Elizabeth J Shpall and Dr. Partow Kebriaei of The University of Texas MD Anderson Cancer Center in Houston; Paul Szabolcs of Duke University Medical Center in Durham, N.C.; Joseph H. Antin of Dana Farber Cancer Institute in Boston, Mass.; Neena Kapoor of Children¹s Hospital of Los Angeles, Keck School of Medicine in California; Sung-Yun Pai of Boston Children¹s Hospital; Scott D. Rowley of John Theurer Cancer Center at Hackensack University Medical Center in New Jersey, and Bimalangshu R Dey of Massachusetts General Hospital.
Funding for this work came from National Institutes of Health-National Heart Lung and Blood Institute grant U54HL08100, the NHLBI funded Production Assistance for Cell Therapies and the National Cancer Institute support grant P30CA125123.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.