Year 3

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, 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). The optimized IL13Rα2-specific CAR T cells mediate potent antitumor activity against preclinical models of GBM. These preclinical studies supported by CIRM have enabled our group to initiate a phase I clinical trial evaluating the safety of single-target IL13Rα2-specific CAR T cells in patients with recurrent GBM. 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.

An important cause of treatment failure to single-target immunotherapy is emergence of antigen negative tumor populations. This process of antigen escape 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 44 patient specimens from the CoH Department of Pathology. Within this group of 79 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.

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.