IMCT-11NEXT GENERATION T CELL RECEPTOR SEQUENCING CAN IDENTIFY, QUANTIFY, AND TRACK TUMOR-SPECIFIC T CELL POPULATIONS BEFORE AND AFTER DENDRITIC CELL VACCINATION IN GLIOBLASTOMA MULTIFORME PATIENTS

Abstract

While dendritic cell vaccination is a promising treatment for glioblastoma (GBM), sensitive methods of monitoring the immune response after treatment remain to be established. We sought to determine whether: 1) T cell receptor (TCR) repertoire overlap between peripheral blood and tumor and 2) tumor infiltrating lymphocyte (TIL) content, as assessed by next generation DNA sequencing, are predictors of immune response and survival. Genomic DNA from pre and post treatment tumor, as well as pre and post treatment peripheral blood, of 16 GBM patients enrolled in Phase I and II DC vaccination clinical trials was subjected to next generation sequencing through the TCRVβ region to quantify TIL content and assess the overlap between tumor and blood. Of the 5 patients for whom initial and relapsed tumors were available, two patients with high TCR sequence overlap between tumor and blood prior to treatment demonstrated the longest overall survival (OS) of 71.3 and 28.7 months. Two patients with poor OS (6.3 and 4.5 months) had low blood and tumor TCR overlap both before and after treatment. One multi-focal recurrent patient with intermediate OS (12.6 months) demonstrated an initially low overlap between pre-treatment tumor and blood; however, the TCR overlap increased 200-fold after treatment. Because we did not possess post-treatment, relapsed tumors for many patients, we tested whether the density of pre-treatment TILs was relevant. For the 16 patients from whom we had pre-treatment tumor tissue, the estimated TIL content significantly correlated with time to progression and OS (HR = 0.252, p = 0.0442; HR = 0.277, p = 0.0461), respectively. The estimated TIL content of pre-treatment tumor directly correlates with survival in GBM patients who received autologous tumor lysate-pulsed DC vaccination. Furthermore, the trends of tumor and peripheral blood TCR overlap suggest that this technology can be utilized to track tumor-specific T cell populations without prior knowledge of their antigen specificity.