Expansion of endogenous T cells in CSF of pediatric and young adult CNS tumor patients undergoing locoregional delivery of IL13R?2-targeting CAR T cells: an interim analysis

Outcomes for pediatric brain tumor patients remain poor, yet there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BB?-CAR T cells delivered weekly into the lateral cerebral ventricles. Our preliminary clinical findings suggest CAR T cell therapy is safe and well tolerated in both lymphodepleted and nonlymphodepleted patients, and may offer modest clinical benefit. In addition to our clinical findings, we carried out a series of correlative analyses leveraging single cell genomics and orthogonal methods to profile PBMCs, mononuclear cells in the cerebrospinal fluid (CSF) and post-treatment tumors. leveraging both single cell genomics and more traditional approaches. These studies identified important interactions between CAR T infusions and the endogenous immune system. Notably, we identified and characterized a population of expanding CAR- CD8+ T cells identified in the CSF. Furthermore, we found these and other immune changes observed in the CSF were not well captured by PBMCs. Conversely, we provide evidence of clonally expanded TCRs shared between CSF and post-treatment tumor. While these data are limited, our findings suggest T cell dynamics observed in the CSF are reflected in the tumor, but not in PBMCs. Taken together, these initial findings provide support for continued investigation into locoregionally-delivered IL13BB?-CAR T cells for children and young adults with brain tumors, and provide important insights into endogenous immune response during therapy. Overall design: This study included scRNA- and scTCR-seq from cerebrospinal fluid (CSF), peripheral blood mononuclear cells (PBMCs), engineered CAR T products, and tumors from 5 pediatric patients with brain tumors as part of an ongoing phase I clinical trial with IL13BB?-CAR T cells. Patient's CSF and PBMCs were sequenced at multiple time points during the course of CAR T treatment. Tumor samples included both pre- and post-CAR T treatment samples. Some patients received lymphodepletion and others did not. Comparisons of scRNA- and scTCR-seq were performed between windows of radiographic response and non-response, among different time points of the CAR T treatment, and between patients that did not receive lymphodepletion and did receive lymphodepletion.