NEW ORLEANS—“Mega-dose” stem cell transplants have been used extensively in patients with acute leukemia over the past decade to overcome rejection and enable transplantation from mismatched family members, when a matched donor is not available. But mismatched transplant recipients are susceptible to life-threatening infections, and the key challenge is to improve immune recovery by administering allogeneic donor T cells without causing graft-versus-host disease (GvHD).
Researchers from Italy have now reported at the ASH Annual Meeting here that an infusion of freshly purified donor T regulatory cells (Tregs) in the setting of mismatched transplantation for high-risk acute leukemia makes administration of high doses of mature T cells feasible, with a low incidence of GvHD.
“Co-infusion of Tregs and mature T cells hastens post-transplant immune reconstitution and reduces the risk of cytomegalovirus reactivation,” said senior author Massimo F. Martelli, MD, Professor and Head of the Section of Hematology and Clinical Immunology at the University of Perugia, speaking at an ASH news conference that featured the study. “More patients and longer follow-up will hopefully show a reduction in transplant-related mortality and better overall survival.
Tregs are a naturally occurring T cell subpopulation, occurring in about 3% to 4% of the peripheral blood, Dr. Martelli said explained. The Phase I/II study, reported at the Plenary Scientific Session as Abstract 4, included 28 patients with high-risk leukemia.
Twenty-six patients achieved full donor-type engraftment. No post-transplant drugs were used to prevent GvHD, and there was no GvHD in 25 patients. The patients made a rapid immune recovery and reported a good quality of life, he said.
In the future, “Tregs might be used to reduce the incidence and severity of GvHD in ‘conventional’ hematopoietic stem cell transplantation, and might eventually be used to induce tolerance in organ transplants,” Dr. Martelli said.
Patients received a conditioning regimen of fludarabine and high-dose radiochemotherapy to eliminate residual leukemic cells and favor engraftment of stem cells from the donor. On the third day, freshly isolated donor Tregs were infused, followed by high doses of purified hematopoietic CD34+ progenitor cells and mature donor T lymphocytes.
Patients did not receive any post-transplant immunosuppression for GvHD prophylaxis. “CD4+ and CD25+ Tregs were easily separated in a fully automated closed system, which reliably yields suitable numbers for the transplant,” Dr. Martelli said. “Three days later, collection started of G-CSF mobilized peripheral blood hematopoietic progenitor cells.”
To remove unwanted T lymphocytes, the CD34+ population, which contains the stem cells, was purified in a fully automated CliniMACS system.
‘High-Risk Hematological Malignancies’
All 28 study patients had high-risk hematological malignancies, many in advanced-stage acute leukemia. None had a matched donor in the family or in the registries. All received a mismatched transplant from a family member.
Still to be demonstrated, Dr. Martelli said, is a reduction in transplant rate mortality and better progression–free survival.
In an OT Broadcast News podcast interview from the meeting, Dr. Martelli said he believes Treg therapy will be used in the future for bone marrow transplantation in hematological non-neoplastic diseases: “I think the main focus will be on diseases such as sickle cell anemia, which is a big problem, and beta thalassemia,” he said.
Preliminary, but Important
The moderator of the news conference, Armand Keating, MD, Professor and Director of the Division of Hematology at the University of Toronto, said in an interview afterwards that he thought the Martelli study was important even though the data are preliminary: “It's very promising, because it looks like regulator T cells may have a therapeutic role in immune modulation. If that can be corroborated, I would say it has the potential to be a landmark.
“And this was done in the context of haplo-identical transplants, where the issue of graft-versus-host disease is a significant condition.”
He said he also thought the new technology potentially might be extended to other types of transplants with fully matched or partially mismatched donors, to reduce the likelihood of acute GvHD and reduce the need for immunosuppression.
A major advantage, he said, would be that immune reconstitution would proceed normally in a situation with a limited extent of depletion.
“Mature T cells could be introduced in those patients, which one would be loathe to do otherwise, because acute graft-versus-host disease could be very serious or fatal,” he said. “But that did not take place in this study.”
Broad-Based Increases in Immune Reconstitution
After Dr. Martelli's oral presentation during the plenary session, session co-moderator and ASH 2009 President Nancy Berliner, MD, Chief of Hematology at Brigham and Women's Hospital and Professor of Medicine at Harvard Medical School, said the major interest in Dr. Martelli's work is the ability to provide broad-based increases in immune reconstitution.
“Selecting Tregs prevents GvHD, but also allows a more rapid reconstitution of the overall immune response, so there were increases in both T cell and B cell responses,” Dr. Berlin said. “Giving even a very small number of unselected T cells almost always causes GvHD and can result in death, certainly in the haplo-identical setting, which is where this study was done.”
Hear Massimo Martelli talk more about his esearch in a “Live from ASH” OT Broadcast News podcast (Program #3) available at oncology-times.com and on iTunes.