Cellular immune biomarkers to prognosticate for survival to adoptive T-cell therapy in advanced nasopharyngeal cancer.

Abstract

6047 Background: We have published a Phase II clinical trial in 35 advanced incurable stage 4c NPC patients employing upfront first line chemo-immunotherapy of four cycles of gemcitabine and carboplatin, followed by six cycles of adoptive transfer autologous EBV-specific cytotoxic T lymphocytes (CTL). The 2- and 3-year overall survival rates were 62.9 and 37.1% respectively, which represent the best reported survival outcome for first-line treatment of advanced NPC when compared to historical clinical trials. Methods: From this Phase II trial, we completed serial multiple deep immune phenotyping analyses including flow cytometry, nanostring, and multiplex ELISA assays. We then investigated how these factors influence and determine successful therapy using 2-year survival rates. Results: Longitudinal modular transcriptome analysis of patient PBMCs revealed significant increases in T cell, NK, and B cell modules post chemotherapy within the 2-year survivor group. Administration of CTLs restored expression of lymphocyte transcripts in the non-survivor group at 2-weeks post infusion. However, as immunotherapy proceeded, 2-year survivors displayed significant increases in multiple lymphocyte module associated transcripts. These immune correlates were associated with increased IFN-γ and decreased myeloid chemokine concentrations in peripheral sera during immunotherapy in 2-year survivors. Longitudinal immunophenotyping of patient PBMCs at serial timepoints showed that 2-year survivors displayed significant decreased amounts of monocytic myeloid-derived suppressor cells (mMDSCs), compared to non-survivors after chemotherapy, which subsequently determined successful CTL immunotherapy survival benefit. Conclusions: This is the first report in human cancer patients that successful adoptive T cell immunotherapy correlates with lower mMDSCs following chemotherapeutic preconditioning. We have also identified potential prognostic immune biomarkers that effectively predicts efficacy of CTL immunotherapy, following upfront combination chemotherapy, and thus survival. Lymphodepletion with chemotherapy appears to be vital for adoptive T cell therapy efficacy.