Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation

Abstract

Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR+ CTLs produced interferon-γ (IFNγ) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 ± 104 to 1034 ± 304 spot-forming cells [SFCs]/105 T cells) and lysed primary B-ALL blasts in 51Cr-release assays (mean, 66% ± 5% specific lysis; effector-target [E/T] ratio, 40:1) and the CD19+ Raji cell line (mean, 78% ± 17%) in contrast to nontransduced controls (8% ± 8% and 3% ± 2%). CB-derived CAR+ CTLs showed similar antiviral and antitumor function and both PB and CB CAR+ CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.