Allogeneic virus-specific T-cell therapy after hematopoietic stem cell transplant: determinants of treatment success and failure - ABSTRACT: Infections caused by double stranded DNA viruses are a common complication after allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 82% of patients undergoing transplant at our institution. These infections are a significant source of both morbidity and mortality in the post-HSCT setting. Commercially available anti-viral medications have inadequate response rates, prolong hospitalizations, and have narrow therapeutic indexes with high toxicity rates. Additionally, there are no effective anti-viral medications for two of the more common viruses, BK polyomavirus (BKPyV) and adenovirus. An alternative approach for viral management is the use of virus-specific T-cells (VST); this cellular therapy approach uses peripheral blood from healthy donors to generate highly expanded and viral directed T-cell populations given as a simple intravenous infusion. This therapy has shown itself across multiple clinical trials to be safe and highly effective for the treatment of viremia and invasive viral disease caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), BKPyV, and adenovirus. The generalizability of this therapy has increased through use of partially-HLA matched, ‘off-the-shelf’ third-party VSTs where a product from a VST bank is chosen for a patient based off of anti-viral activity of the product and the degree of human leukocyte antigen (HLA) matching. However, while response rates are excellent (on the order of 70-90% depending on the virus), treatment failures occur even when a good and rationally chosen product is given. In this proposal we aim to improve understanding of the mechanisms underlying treatment success and failure following VST infusion. We hypothesize that both patient- and virus- specific factors facilitate the effective response to third-party VSTs and that treatment non-response is due to definable and non-mutually exclusive defects in one or both of these areas. We will use pre- and post-infusion samples collected from patients enrolled on an active third-party VST treatment study to complete these aims. From a recipient perspective, we believe that failure of VST persistence, inadequate antigen presentation, and failure of initial T-cell expansion can be detected in patients with poor response. From a viral perspective, we will use epitope mapping and NGS sequencing of viral genome to explore the role of both non-conservation of antigenic epitopes and antigen escape. We believe that these experiments will generate generalizable data on mechanisms behind VST treatment with potential implications for improving the therapy moving forward.
