Graft Versus Leukemia Response Without Graft-versus-host Disease Elicited By Adoptively Transferred Multivirus-specific T-cells

Abstract

A 12-year-old boy with refractory acute lymphoblastic leukemia received a haploidentical transplant from his mother. As prophylaxis for Epstein-Barr virus (EBV), cytomegalovirus (CMV) and adenovirus, he received ex vivo expanded virus-specific donor T cells 3.5 months after transplant. Four weeks later leukemic blasts bearing the E2A deletion, identified by fluorescent in situ hybridization (FISH), appeared transiently in the blood followed by a FISH-negative hematological remission, which was sustained until a testicular relapse 3.5 months later. Clearance of the circulating leukemic cells coincided with a marked increase in circulating virus-specific T cells. The virus-specific cytotoxic T-cell (CTL) line showed strong polyfunctional reactivity with the patient's leukemic cells but not phytohemagglutinin (PHA) blasts, suggesting that virus-specific CTL lines may have clinically significant antileukemia activity.

Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation

“…Only four responders had recurrence or progression. GvHD developed in eight patients (two of them showed de novo GvHD, and in only one of grade 3) confirming previous observations [107,108]. Most interestingly, the VSTCs used in this study were "off-the-shelf" and only partially HLA-matched.…”

CMV-specific T cells generated from naïve T cells recognize atypical epitopes and may be protective in vivo

“…Functionality of the T-cells was assessed by the flow cytometric detection of intracellular accumulation of IFN-γ, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α), and CD40 ligand (CD40L) (all from BD Biosciences) as previously described. (48, 49) Briefly, T-cells were stimulated with 1 μg/mL final concentration of each Pepmix; medium alone was used as the negative control. After incubation for 1 hour at 37°C, 10 μg/mL of Brefeldin A (Sigma) was added for an addition 5 hours.…”

Improving the safety of T-Cell therapies using an inducible caspase-9 gene

“…Antigen-specific T cells such as virus-specific cytotoxic T lymphocytes can expand in vivo, actively traffic to tumor sites, expand upon exposure to antigens, and persist long term. Moreover, activated T cells can recruit additional and distinct sets of cellular and cytokine-mediated effector mechanisms once antigen is recognized [5–8]. Given the desirable properties of these cell therapies, there has been great interest in adoptively transferring T cells capable of recognizing and destroying human tumors.…”