Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted
Jeremy D. Rubinstein, Xiang Zhu, Thomas Leemhuis, Giang Pham, Lorraine Ray, Sana Emberesh, Sonata Jodele, Shawn Thomas, José A. Cancelas, Catherine M. Bollard, Patrick J. Hanley, Michael D. Keller, Olivia Grimley, Diana Clark, Teri Clark, Cecilia S. Lindestam Arlehamn, Alessandro Sette, Stella M. Davies, Adam S. Nelson, Michael Grimley, Carolyn Lutzko
Abstract
Infection with adenoviruses is a common and significant complication in pediatric patients after allogeneic hematopoietic stem cell transplantation. Treatment options with traditional antivirals are limited by poor efficacy and significant toxicities. T-cell reconstitution is critical for the management of adenoviral infections, but it generally takes place months after transplantation. Ex vivo-generated virus-specific T cells (VSTs) are an alternative approach for viral control and can be rapidly generated from either a stem cell donor or a healthy third-party donor. In the context of a single-center phase 1/2 clinical trial, we treated 30 patients with a total of 43 infusions of VSTs for adenoviremia and/or adenoviral disease. Seven patients received donor-derived VSTs, 21 patients received third-party VSTs, and 2 received VSTs from both donor sources. Clinical responses were observed in 81% of patients, with a complete response in 58%. Epitope prediction and potential epitope identification for common HLA molecules helped elucidate HLA restriction in a subset of patients receiving third-party products. Intracellular interferon-γ expression in T cells in response to single peptides and response to cell lines stably transfected with a single HLA molecule demonstrated HLA-restricted CD4+ T-cell response, and these results correlated with clinical outcomes. Taken together, these data suggest that VSTs are a highly safe and effective therapy for the management of adenoviral infection in immunocompromised hosts. The trials were registered at www.clinicaltrials.gov as #NCT02048332 and #NCT02532452.