Third-Party BK Virus-Specific Cytotoxic T Lymphocyte Therapy for Hemorrhagic Cystitis Following Allotransplantation

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.

Generation of glucocorticoid-resistant SARS-CoV-2 T cells for adoptive cell therapy

“…The effector phenotype predicts the capacity to mediate early viral clearance, whereas CM T cells persist and provide long-term immunity after adoptive transfer (Powell et al, 2005). Indeed, our group and others have confirmed that adoptive infusion of VSTs with a predominantly CD4+ EM phenotype results in successful eradication of severe viral infections such as JCV, BKV, and adenovirus (Heslop et al, 2010;Leen et al, 2010;Muftuoglu et al, 2018;Olson et al, 2021). We also investigated the functional state of SARS-CoV-2 T cells based on their ability to produce one or more cytokines in response to ex vivo stimulation with SARS-CoV-2 Cell Reports 36, 109432, July 20, 2021 7 Article ll OPEN ACCESS antigens.…”

Optimization of Donor Lymphocyte Infusion for AML Relapse After Allo-HCT in the Era of New Drugs and Cell Engineering

“…Recently, thirdparty pathogen-specific cytotoxic T cells have been developed for off-the-shelf use. Olsen et al reported a trial using third-party BK virus-specific cytotoxic T cell infusions into 59 patients developing BK virus-associated hemorrhagic cystitis after allo-HCT, and a day 14 overall response rate of 67.7% was observed (69). Moreover, several techniques are being investigated for optimal T cell allodepletion with preservation of pathogenspecific responses and Tregs (70).…”

Case Report: Fatal Complications of BK Virus-Hemorrhagic Cystitis and Severe Cytokine Release Syndrome Following BK Virus-Specific T-Cells

“…Using HSCT-donor derived VSTs, Nelson et al found that 87% of patients with BK viremia and/or HC (n=38) responded to ≥1 anti-BK VST infusions; 58% completely cleared BKV and demonstrated resolution of HC symptoms ≤ grade II (10). Olson et al describe comparable outcomes with HLA-matched third-party anti-BK VSTs (21). Infusion-related adverse events were rare with HSCT-donor derived or third-party VSTs (10,21).…”

“…Olson et al describe comparable outcomes with HLA-matched third-party anti-BK VSTs (21). Infusion-related adverse events were rare with HSCT-donor derived or third-party VSTs (10,21).…”