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

Autor: Ala Abuddayeh, Uday R. Popat, Chitra Hosing, Betul Oran, Amin M. Alousi, Katayoun Rezvani, Peter F. Thall, Partow Kebriaei, Roy B. Jones, Borje S. Andersson, Indreshpal Kaur, Mustafa Bdaiwi, Li Li, Melissa Timmons, Amanda Olson, Stefan O. Ciurea, Roy F. Chemaly, David Marin, Richard E. Champlin, Sairah Ahmed, Glorette Abueg, Elizabeth J. Shpall, Ruitao Lin, Hind Rafei
Rok vydání: 2019
Předmět:
Zdroj: Blood. 134:3596-3596
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2019-126028
Popis: Background. BK virus associated hemorrhagic cystitis (BKV-HC) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT), [Bedi, A., et al. JCO 1995] particularly in recipients of alternative donor transplants, which are being performed with increasing frequency [O'Donnell, P.H., et al, BBMT 2009]. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, with few effective therapeutic options [Seber, A., et al., BMT 1999]. Methods. We assessed the feasibility, safety, and efficacy of administering most closely human leukocyte antigen (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 47 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. We compared their toxicity and survival to a control group of 85 AHSCT patients with BKV-HC treated with standard of care, using inverse probability of treatment weighted (IPTW) estimation to correct for bias due to non-randomization. The control group was matched for age, gender, graft versus host disease prophylaxis, conditioning regimen, AHSCT graft source, and both initial and maximum grade of BKV-HC. Results. On average, BKV disease status improved from 7 to 90 days post CTL infusion, with the primary response endpoint scored on day 28. Among 31 evaluable patients on day 28 who received a single BKV CTL infusion, 18 had a complete response (CR) and 9 a partial response (PR), for an overall response rate of 87%, which increased to 100% among evaluable patients at day 90 (Figure 1). Four of 7 patients who received multiple (1-5) CTL infusions for persistent disease following the first infusion are alive without BKV-HC. Median survival from the date of transplant in the BKV CTL group was 772 days, compared to a median of 171 days for the controls (IPTW adjusted log rank test p-value = 0.02) as shown in Figure 2. One BKV CTL patient with a history of skin graft versus host disease (GVHD) developed grade 3 gastrointestinal GVHD 64 days post CTL infusion, which resolved completely with systemic steroids. There were no cases of graft failure or infusion-related toxicities. BKV CTLs were identified in patient blood samples up to one month post-infusion. Conclusion. This is the largest series of AHSCT patients treated to date with BKV CTLs. The high response rate we observed in this study appeared to confer a survival benefit compared to a historically controlled cohort with BKV-HC treated with standard of care alone. This study demonstrated that administering third party, off-the-shelf banked BKV CTLs is feasible and safe. The safety profile, high response rate, and logistical ease with which potent off-the-shelf BKV CTL therapy were generated and administered warrants further investigation for patients with BKV-HC who have limited alternative therapeutic options. Disclosures Chemaly: ADMA Biologics: Other: Personal fees; Gilead: Research Funding; Janssen: Other: Personal fees; Ansun: Other: Personal fees; Oxford Immunotec: Research Funding; Chimerix: Research Funding; Ablynx: Other: Personal fees; Merck: Research Funding; Clinigen: Other: Personal fees; Gilead: Other: Personal fees; Ansun Pharmaceuticals: Research Funding; Chimerix: Other: Personal fees; Oxford Immunotec: Other: Personal fees; Merck: Other: Personal fees; ReViral: Other: Personal fees. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Jazz: Consultancy; Pfizer: Honoraria; Amgen: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Champlin:Sanofi-Genzyme: Research Funding; Actinium: Consultancy; Johnson and Johnson: Consultancy.
Databáze: OpenAIRE
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