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.
Under this CIRM Early Translational Award, our group has developed and optimized a next-generation adoptive T cell therapy platform for targeting the glioma-associated antigen IL13Rα2. As such, T cells are 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. Initial clinical finding are highly promising, as repetitive local intracranial delivery of IL13Rα2-specific CAR T cells has been safe and encouragingly demonstrated antitumor activity for some patients. 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. Based on the evaluation of a panel of patient-derived GBM specimens, we have cataloged patterns of expression between patients and within tumors, identifying IL13Rα2, HER2 and EGFR as attractive targets for our proposed combination immunotherapy. We have optimized the CAR T cell clinical development candidate to target HER2 and defined an EGFR-CAR that recognizes mutated (i.e., EGFRvIII) and amplified EGFR. Importantly, we show in preclinical models that combination targeting of IL13Rα2, HER2 and EGFRvIII/amp improves antitumor responses and durability of response over single antigen targeting. Our achievements under this CIRM Early Translational Award sets 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.