Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation
Amanda Olson, Ruitao Lin, David Marín, Hind Rafei, Mustafa Bdiwi, Peter F. Thall, Rafet Başar, Ala Abudayyeh, Pinaki P. Banerjee, Fleur M. Aung, Indresh Kaur, Glorette Abueg, Sheetal Rao, Roy F. Chemaly, Victor E. Mulanovich, Gheath Alatrash, Amin M. Alousi, Börje S. Andersson, Paolo Anderlini, Qaiser Bashir, Karla Castro, May Daher, Isabel M. Galvan, Chitra Hosing, Jin S. Im, Roy B. Jones, Partow Kebriaei, Issa F. Khouri, Rohtesh S. Mehta, Jeffrey J. Molldrem, Yago Nieto, Betül Oran, Uday Popat, Muzaffar H. Qazilbash, Gabriela Rondón, Neeraj Saini, Bryan R. Spencer, Samer A. Srour, Dominique Washington, Melissa Barnett, Richard E. Champlin, Elizabeth J. Shpall, Katayoun Rezvani
Abstract
PURPOSE: BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS: We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS: Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION: Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.