ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).
Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.