Use of highly characterized EBV-Specific T Cells outside of the immediate Post-Transplant setting

Abstract

Background & Aim Given the efficacy of donor-derived EBV-specific T cells (EBVSTs) in the post- HSCT environment, and considering many lymphoma patients are immunocompromised, we hypothesized that third-party EBVSTs can effectively treat EBV+ lymphoma by directly killing lymphoma cells, and by reactivating endogenous immunity. To test this hypothesis, we designed a Phase 1 dose escalation trial (in accordance with regulatory agencies) of third party EBVSTs in patients with relapsed/refractory EBV+ lymphoma. Methods, Results & Conclusion We generated a bank of EBVSTs from eligible donors with diverse HLA haplotypes and highest antigen specificity to the EBV Type 2 latency antigens (LMP1/2, EBNA1, BARF1) using IFNγ ELIspot assay. We constructed a database containing the HLA restriction of antigen specificity for each line to ensure we only choose lines with antigen-specific activity restricted by alleles shared between donor and recipient. We identified a suitable partially matched line for 94% of referred patients within 2 days. We have treated 19 patients, 14 of which are evaluable. At the initial response evaluation timepoint, 8 of these 14 patients had a clinical response (complete, partial, or mixed responses), which was sustained for at least 6 months in 5 patients. Additionally, 4/14 patients experienced prolonged stable disease, despite previous refractory status. Infusions were safe, with no occurrences of graft-versus host disease or cytokine release syndrome. We observed enhanced and sustained viral and non-viral tumor antigen recognition in most responding patients, and early loss of antigen recognition in the 2 patients with progressive disease. Using technology from Adaptive Biotechnologies, we tracked the frequency of patient and line-specific clones at post-infusion timepoints in a subset of patients. While this analysis is still ongoing, early anaylsis indicates that some patients with favorable clinical responses had EBVST clones from the infused line that were identified at both early and late time points. Expansion corresponded with increased responses to EBV or tumor-associated antigens on ELIspot assays, suggesting EBVSTs may act as a “vaccine” for functional clones. We are exploring strategies to enhance persistence and antitumor activity, including lymphodepleting chemotherapy and engineering our T cells resistant to alloreactive rejection. Given the promising responses, we have recently extended our therapy to other EBV+ malignancies.