Development of combinatorial EGFRviii/lL13Ra2 directed Chimeric Antigen Receptor T-cell therapy in Glioblastoma

Led by: Dr. Michael Ruff


A new form of therapy to treat cancer has emerged called Chimeric Antigen Receptor T-cell therapy, or CAR-T. CAR-T uses the patient’s own white blood cells which are then genetically modified to attach an antibody to the T-cell which is specific to a tumor marker. The antibody is coupled to a signaling cascade within the T-cell to activate it and engage the immune response. This creates, in essence, a living drug that can survive in a patient to prevent disease recurrence. The first FDA approval of this therapy was in 2017, approved for the treatment of lymphoma and a type of leukemia. Additionally, CAR-T technology has been demonstrated to have a dramatic effect against glioblastoma targeting a tumor specific marker, IL-13Ra2. Another recent case series of patients with glioblastoma treated with a CAR-T targeting a different tumor cell marker (EGFRviii) was recently published and seems to reinforce that there is efficacy against glioblastoma with this method of treatment. A major barrier with previous targeted treatment in glioblastoma has been the diversity of the tumor cell population. For example, not all tumor cells in a patient’s tumor will express EGFRviii or IL-13Ra2 and therefore CAR-T targeting one of the two targets leads to escape of those cells that do not express the CAR-T target. Our group’s novel approach is to combine these two previously published (and safe in human) targets for CAR-T (IL 13Ra2 and EGFRviii) to create a dual antigen CAR so as to increase the targeting efficiency of this mode of therapy. We are ready to begin evaluation of this dual construct against tumor cells that have either target on them. We are preparing to demonstrate that our construct can correctly recognize and kill glioblastoma cells with either marker; specifically, we will look to see if the use of our construct prolongs the survival of mice implanted with glioblastoma cell lines, prior to initiating a phase 1 clinical trial in human beings. We hypothesize that a dual antigen CAR such as ours will be more efficacious than prior CAR-T cells in glioblastoma and have minimal systemic toxicity.