Differential antibody response to EBV proteome following EBVST immunotherapy in EBV-associated lymphomas.

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV-antigen specific antibody responses associated with clinical outcomes, we comprehensively characterized the antibody responses to the complete EBV proteome using a custom protein microarray in 56 EBV-associated lymphoma patients who received EBVST infusions enrolled in Phase I clinical trials. Responders (non-progressors) and non-responders (progressors) had distinct antibody profiles against EBV. Twenty-five IgG antibodies were significantly elevated in higher levels in non-responders compared to responders at 3 months post-EBVST infusion. Ten of these remained significant after adjustment for sex, age, and cancer type, including LMP2A (four variants), BGRF1/BDRF1 (two variants), LMP1, BKRF2, BKRF4, and BALF5. Random forest analysis identified these 10-IgG antibodies as key predictors of clinical response. Paired analyses using blood samples collected at both pre-infusion and 3 months post-EBVST infusion indicated an increase in the mean antibody level for six other anti-EBV antibodies (IgG: BGLF2, LF1, BGLF3; IgA: BGLF3, BALF2, BBLF2/3) in non-responders. Overall, our findings suggest that these EBV-directed antibodies as potential serological markers for predicting clinical responses to EBVST infusions and as therapeutic targets for immunotherapy in EBV-positive lymphomas. NCT01555892 - Cytotoxic T-Lymphocytes for EBV-positive Lymphoma, GRALE NCT02973113 - Nivolumab With Epstein Barr Virus Specific T Cells (EBVSTS), Relapsed/Refractory EBV Positive Lymphoma (PREVALE) NCT02287311 - Most Closely Matched 3rd Party Rapidly Generated LMP, BARF1 And EBNA1 Specific CTL, EBV-Positive Lymphoma (MABEL).