California's Stem Cell Agency

While current treatment strategies for glioblastoma (GBM) can yield short term benefits, their inability to eradicate the highly tumorigenic cancer stem cell population results in disease recurrence in the vast majority of patients. Stem cells and some cancer cells (the targets of our therapy) share many common characteristics, including the ability to self-renew and grow indefinitely. These stem cell-like cancer cells are also resistant to many standard therapies including radiation and chemotherapy, creating a critical need for novel therapies that will efficiently eliminate this cell population. The goal of this project is to develop and optimize a therapeutic strategy, termed “adoptive T cell therapy,” that will eliminate the brain tumor stem cell population by re-directing a patient’s immune cells, specifically T cells, to recognize and destroy tumor stem cells. Our goal is a therapy in which administration of tumor-specific T cells targeting combinations of antigens expressed on the cell surface of glioma stem-like cells results in long-term anti-glioma protection. Our approach builds on our previous pre-clinical and clinical findings that T cells, when reprogrammed, can potently kill glioma stem cells. Thus far, our group has developed and characterized an optimized next-generation adoptive T cell therapy platform for targeting the glioma-associated antigen IL13Rα2. As such, T cells were modified to express a chimeric antigen receptor (CAR) to recognize and kill IL13Rα2-expressing glioma cells. This T cell platform incorporates several improvements in CAR design and T cell engineering over previous versions, including improved receptor signaling and the utilization of central memory T cells (Tcm) as the starting cell population for CAR-engineering (enhancing long-term persistence of the cells after they are administered to patients). Importantly, we now demonstrate that this optimized IL13Rα2-specific CAR Tcm therapeutic product mediates superior antitumor efficacy and improved T cell persistence as compared to our previous first-generation IL13Rα2-specific T cells. We further demonstrate that intracranial (i.c.) delivery of the IL13Rα2-specific CAR T cells outperforms intravenous (i.v.) delivery in orthtotopic mouse models of human glioblastoma, providing the clinical rational for local i.c. delivery. These findings are significant as they suggest the potential of this optimized next-generation platform to improve upon the transient anti-glioma patient responses observed in two Phase I clinical trials completed by our group at City of Hope. Based on these earlier results we have submitted an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to initiate a single agent IL13Rα2-specific CAR T cell clinical trial. This clinical trial will provide a foundation for the ultimate goal of this CIRM ET award: development of a combination CAR T cell approach to overcome the high-degree of GBM heterogeneity. This antigenic variability of gliomas, including differences between populations of glioma stem-like cells, is a critical barrier to the development of an immunotherapy with the potential to mediate complete and durable disease remission. We hypothesize that a multi-targeted therapeutic approach will be required to achieve elimination of glioma stem-like cells and achieve longer lasting regression of high-grade glioma. To devise an effective multi-target therapy, we are first identifying potentially useful T cell target antigens, and assessing variations in their expression between patients and within individual tumors. Ideal targets will be highly expressed on tumor cells, including stem-like cells, and not found on normal brain or other tissues. To this end, we have assembled a cohort of 35 patient samples in commercial tissue arrays and 45 patient specimens from the CoH Department of Pathology. Within this group of 80 patient tumors we have been examining expression of potential T cell targets, such as IL13Rα2, HER2, EGFR/EGFRvIII, and others. Our goal is to define a set of target antigens encompassing the maximum number of tumors and, in particular, the cancer stem-like cells within individual tumors. Based on this analysis, we are currently developing and optimizing CAR T cells targeting HER2 and EGFRvIII. Our progress is thus continuing to set the stage for developing a potent multi-antigen specific T cell therapy that can “box-in” tumor variability. Our clinically translatable platform has the potential to provide new treatment options for this devastating disease.