Work

5: Long-Term Follow-Up of Administration of Donor-Derived EBV-Specific CTLs to Prevent and Treat EBV Lymphoma After Hemopoietic Stem Cell Transplant

Year: 2008

Type: article

Abstract: Since 1993 we have administered polyclonal donor-derived EBV-specific CTLs to high-risk recipients after HSCT. A total of 73 patients have received CTLs, 66 as prophylaxis and 7 as therapy. 11 patients had underlying primary immunodeficiencies (6 XLP, 1 WAS, 2 undefined CID, 2 CAEBV), and 5 had developed EBV-associated LPD or HLH which was controlled prior to HSCT. None of the patients on the prophylaxis study had any acute toxicity and only 2 patients developed exacerbations of previously existing GVHD month after infusion. Local inflammation during a therapeutic response was seen in 3 patients who had high EBV DNA and likely had undiagnosed LPD prior to receiving CTLs. All recovered with no active intervention and had no long term sequelae. 6 patients have been treated for established EBV lymphoma, with complete responses seen in 5, accompanied by accumulation of gene-marked CTL at sites of disease. In 1 patient with extensive disease significant inflammation was seen at sites of disease after CTL administration illustrating the benefits of treating patients with early disease. The patient who failed treatment was found to have a mutation resulting in deletion of the two 2 immunodominant HLA11 restricted epitopes in EBNA 3B, recognized by the donor CTL line. In the first 26 patients CTLs were marked with the neomycin resistance gene to track their fate and persistence and 17 of these 26 patients are alive from 11 to 14 years post CTLs with the remaining 9 patients dying from relapse (n = 6) infection (n = 2) and a motor vehicle accident (n = 1). No RCR has been detected and no patient has developed any new malignancies although 1 patient had recurrence of a pre-existing non hematologic malignancy which was negative for the marker gene by PCR analysis. Analysis of DNA using a real time PCR assay has shown detection of the marker gene for up to 85 months with intermittent detection in peripheral blood T-cells. The gene-modified EBV-CTL population expanded in vivo directly after infusion and also at later times in response to EBV-reactivation, contracting when the antigenic stimulus subsided. Integration site analysis performed on peripheral blood samples has shown polyclonal cell populations with no gene or genomic locus appearing to be preferentially selected by retroviral integration. EBV-specific CTLs can therefore restore anti-viral immunity and mediate antitumor effects with an excellent safety profile on long term follow up.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2007.12.012