Third-Party and Patient-Specific Donor-Derived Virus-Specific T Cells Demonstrate Similar Efficacy and Safety for Management of Viral Infections after Hematopoietic Stem Cell Transplantation in Children and Young Adults

Thomas J. Galletta, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Thomas.Galletta@cchmc.org.
Adam Lane, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Carolyn Lutzko, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divison of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Hoxworth Blood Center, University of Cincinnati, Cincinnati, Ohio.
Thomas Leemhuis, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Hoxworth Blood Center, University of Cincinnati, Cincinnati, Ohio.
Jose A. Cancelas, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divison of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Hoxworth Blood Center, University of Cincinnati, Cincinnati, Ohio.
Ruby Khoury, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
YunZu M. Wang, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Patrick J. Hanley, Center for Cancer and Immunology Research, Children's National Hospital and Department of Pediatrics, The George Washington University, Washington, DC.
Michael D. Keller, Center for Cancer and Immunology Research, Children's National Hospital and Department of Pediatrics, The George Washington University, Washington, DC.
Catherine M. Bollard, Center for Cancer and Immunology Research, Children's National Hospital and Department of Pediatrics, The George Washington University, Washington, DC.
Stella M. Davies, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Michael S. Grimley, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Jeremy D. Rubinstein, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Document Type

Journal Article

Publication Date

2-3-2023

Journal

Transplantation and cellular therapy

DOI

10.1016/j.jtct.2023.01.027

Abstract

Infections with double-stranded DNA viruses are a common complication after hematopoietic stem cell transplantation (HSCT) and cause significant morbidity and mortality in the post-transplantation period. Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and young adults. Owing to a greater degree of HLA matching between the recipient and stem cell donor, DD VSTs potentially persist longer in circulation compared to TP VSTs, because they are collected from a well-matched donor. However, TP VSTs are more easily accessible, particularly for smaller transplantation centers that do not have VST manufacturing capabilities, and more economical than creating a customized product for each transplant recipient. We conducted the present study to compare clinical efficacy and safety outcomes for DD VSTs and TP VSTs in a large cohort of pediatric and young adult HSCT recipients and to determine whether DD VSTs are associated with improved outcomes owing to potentially longer persistence in the recipient's circulation. This retrospective cohort study included 145 patients who received VSTs at Cincinnati Children's Hospital Medical Center (CCHMC) between 2017 and 2021 for the treatment of adenovirus, BK virus, cytomegalovirus, and/or Epstein-Barr virus. Viruses were detected using quantitative polymerase chain reaction. Patients received VSTs on a DD (NCT02048332) or TP (NCT02532452) protocol, and VST products for both protocols were manufactured in an identical fashion. The primary study outcome was clinical response to VSTs, evaluated 4 weeks after VST administration, defined as decrease in viral load to under the inclusion thresholds or resolution of symptoms of invasive viral infection without the need for additional conventional antiviral medication following VST administration. Secondary outcomes included graft-versus-host disease, transplant-associated thrombotic microangiopathy, renal function, hospital length of stay, and overall survival at 30 days and 100 days after VST administration and 1 year after HSCT. Statistical analysis was performed using the Fisher exact test or chi-square test. An unpaired t test was used to compare continuous variables. The study group comprised 77 patients in the DD cohort and 68 patients in the TP cohort. Eighteen patients in the TP cohort underwent HSCT at CCHMC, and the other 50 underwent HSCT at other institutions and presented to CCHMC solely for VST administration. There was no statistically significant difference in clinical response rates between DD and TP cohorts (65.6% versus 62.7%; odds ratio [OR], 1.162; 95% confidence interval [CI], .619 to 2.164; P = .747). There were no significant differences in secondary outcomes between the 2 cohorts. The percentage of patients requiring multiple infusions for a clinical response did not differ significantly between the DD and TP cohorts (38.2% versus 32.5%; OR, .780; 95% CI, .345 to 1.805; P = .666). We found no significant difference in clinical response rate between DD VSTs and TP VSTs and a similar safety profile. Our data suggest that TP VSTs may be sufficient to control viral infection until immune reconstitution occurs despite the potential for more rapid VST clearance compared to DD VSTs. The lack of significant differences between DD VSTs and TP VSTs is an important finding, indicating that it is not necessary for every transplant center to manufacture customized DD VSTs, and that TP VSTs are a satisfactory substitute.

Department

Pediatrics

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