Immunity, Homing and Efficacy of Allogeneic Adoptive Immunotherapy for Posttransplant Lymphoproliferative Disorders

Abstract

Adoptive immunotherapy using autologous EpsteinBarr virus (EBV)-specific cytotoxic T-lymphocytes (auto-CTL) can regress posttransplant lymphoproliferative disorders (PTLD). Widespread applicability of auto-CTL remains constrained. Generation is timeconsuming, and auto-CTL cannot be established in patients treated with the B-cell depleting antibody rituximab. By contrast, pregenerated allogeneic CTL (allo-CTL) offers immediate accessibility. Allo-CTL has previously shown efficacy in "early" polyclonal-PTLD. We treated three patients with aggressive, advanced monoclonal-PTLD following solid-organ transplantation. All were refractory to at least three prior therapies. Despite HLA disparity, there was negligible toxicity, with early in vivo antiviral efficacy and reconstitution of EBV peptide-specific immunity. Two patients attained complete remission (CR). One remains in CR 17 months following therapy, coincident with persistence of donor-derived tumor targeted EBV-specific CTL; the other died of non-PTLD related pathology. In the third patient, autopsy demonstrated homing of allo-CTL at the tumor site. Larger prospective studies of EBV-specific allo-CTL in PTLD are warranted.

Using Epstein-Barr Viral Load Assays To Diagnose, Monitor, and Prevent Posttransplant Lymphoproliferative Disorder

“…However, restoring immunity alone may be insufficient, and the risk of graft rejection calls for careful consideration of all available therapies. Complementary interventions include infusing donor lymphocytes (typical healthy donor mononuclear cells are comprised of about 5% EBV-directed cells) (17), infusing EBV-specific cytotoxic T cells that are grown ex vivo by exposing HLA-matched T cells to EBV antigens (37,64,79,85,168), and infusing anti-CD20 monoclonal antibody (e.g., rituximab) (33,60,71,72,171,197). If initial intervention is insufficient, more traditional cancer treatment with radiation and multidrug chemotherapy is used (135,190).…”

T-cell therapy: the next generation

“…Of note, no patient developed graft-versus-host disease post-CTL administration. Similar positive outcomes were reported in two solid-organ recipients with CNS lymphoma who received closely matched EBV-specific T cells resulting in complete resolution of their brain lesions [21]. Based on this promising data, we recently initiated a Phase I multicenter trial to evaluate banked trivirusspecific CTLs into third-party HSCT recipients with encouraging early clinical results in five out of eight evaluable recipients with serious viral disease.…”

Can a blood test monitor lymphoma?

“…Theoretically, a decrease in viral load suggests a decrease in tumor burden; however, if samples are taken immediately after treatment, it is plausible that the EBV DNA load will spike as tumor cells apoptose. For instance, we observed that EBV DNA viral load significantly increased in patients with PTLD immediately postadoptive T-cell therapy and then returned to undetectable levels prior to subsequent infusions [15]. The kinetics of EBV DNA viral load is unknown, and a more thorough understanding is required.…”