CAR T cell therapy drives endogenous locoregional T cell dynamics in a responding patient with glioblastoma

Abstract

CAR T cell therapy has transformed clinical care and management of patients with certain hematological cancers. However, it remains unclear whether the success of CAR T cell therapy relies solely on CAR T cell engagement with tumor antigen, or if it also requires the stimulation of an individual patients endogenous T cell response. Here, we performed combined analysis of longitudinal, single cell RNA and T cell receptor sequencing on glioblastoma tumors, peripheral blood (PB), and cerebrospinal fluid (CSF) from a patient with recurrent multifocal glioblastoma that underwent a remarkable response followed by recurrence on IL13RA2-targeted CAR T cell therapy (Brown et al. 2016). Single cell analysis of a tumor resected prior to CAR T cell therapy revealed the existence of an inflamed tumor microenvironment including a CD8+ cytotoxic, clonally expanded and antigen specific T cell population that disappeared in the recurrent setting. Longitudinal tracking of T cell receptors uncovered distinct T cell dynamics classes in the CSF during CAR T cell therapy. These included T cell clones with transient dynamics, representing intraventricular CAR T cell delivery and endogenous T cell recruitment from the PB into the CSF; and a group of T cells in the cerebrospinal fluid, that tracked with clonally expanded tumor resident T cells and whose dynamics contracted concomitantly with tumor volume. Our results suggest the existence of an endogenous T cell population that was invigorated by intraventricular CAR T cell infusions, and combined with the therapy to produce a complete response.