Adoptive transfer of IL13Rα2-specific T cells for the treatment of glioblastoma: building on clinical achievements with second-generation CARs

Abstract

The poor prognosis for patients with malignant glioma (MG) is largely attributable to invasive therapy-resistant malignant cells responsible for tumor recurrence. Adoptive immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) may be an effective and safe strategy for reducing disease recurrence. Our group has developed a CART cell immunotherapy targeting IL13Ralpha2, a receptor over-expressed by a high percentage of MGs. In two previous phase I clinical trials evaluating first-generation IL13Ralpha2-CAR T cells, we demonstrated the feasibility of this approach, showing an absence of serious therapy-related side-effects and evidence for transient anti-glioma responses. Building on this experience, we have now developed an optimized CAR T cell product incorporating enhancements in CAR design and T cell engineering, which improve T cell persistence and antitumor potency. These include a second-generation CAR containing the 41BB (CD137) costimulatory signaling domain (IL13BBzeta-CAR), and a manufacturing strategy using an enriched central memory T cell (Tcm) population for genetic engineering. In orthotopic IL13Ralpha2+ MG mouse models, single injection of optimized IL13BBzeta-CAR Tcm resulted in robust antitumor activity and significantly improved T cell persistence compared to first-generation IL13Ralpha2-CAR T cells. We also found that IL13BBzeta-CAR T cells administered by intracranial (i.c.) delivery outperformed intravenous delivery in MG xenograft mouse models, and were able to eradicated tumors at the primary tumor site and then traffic to tumors in the contralateral hemisphere, providing evidence for CAR T cell targeting of invasive multi-focal disease. Finally, we demonstrated that the optimized IL13BBzeta-CAR Tcm, which recognize IL13Ralpha2 via a membrane-tethered IL 13 ligand mutated at a single site (E13Y), exhibited preferential recognition of IL13Ralpha2 and decreased recognition of the more ubiquitously expressed IL13Ralpha1. In summary, these studies support the clinical applicability of this optimized IL13BBzeta-CAR Tcm therapeutic product for the treatment of MG.