Engineering the CAR T Cells to Overcome Tumor Derived Immune-Inhibition in Glioblastoma
Background: Outcome for children with glioblastoma (GBM) is extremely poor. It is highly resistant to conventional methods of cancer treatment and less than 16% of children survive more than five years after diagnosis. In addition, aggressive combined therapy causes significant harm. Recent advancements in cancer immunotherapy have enabled us to genetically engineer patients' own T cells to express artificial molecules called chimeric antigen receptors (CARs) that specifically recognize the GBM-associated protein, human epidermal growth factor receptor 2 (HER2). A phase I trial for HER2 immunotherapy was safe with no treatment-related toxicities and offered clinical benefit to 50% of treated patients. To put our results in perspective, the median survival doubled compared to the other salvage interventions for GBM patients failing front-line therapy. However, there is a need to improve the killing activity of these T cells, since tumor-derived immune-inhibitory molecules present at the tumor site can turn-off these cells upon encounter. Blocking this immune-checkpoint using monoclonal antibodies has improved outcomes for a subset of resistant cancers, but the best means for overcoming this tumor derived inhibitory mechanism in the central nervous system (CNS) is largely unknown at present.
Project Goal: Our methodology will enable the T cells to kill GBM cells expressing HER2 and overcome/transform the immune-checkpoint in favor of T cells without organ-system toxicities. This study has the potential to dramatically improve outcomes for GBM patients upon translation in to a clinical trial and advance information leading to future standards in pediatric brain tumor immunotherapy.
Project Update 2021: Recent advancements in cancer immunotherapy have enabled us to genetically engineer patients’ own T cells to express artificial molecules called chimeric antigen receptors (CARs) that specifically recognize the tumor-associated protein, human epidermal growth factor receptor 2 (HER2). A phase I trial for HER2-CAR T-cell therapy was safe in patients with GBM and offered clinical benefit to 50% of treated patients. However, to achieve sustained clinical benefit, there is a need to improve the function of HER2-CAR T cells. The immune-inhibitory molecules present in the tumor can turn-off the T cells resulting in poor function. One such major mechanism in GBM is PD-L1/PD-1 immune-checkpoint. PD-1/PD-L1 checkpoint inhibitors have improved outcomes for a subset of resistant cancers, but the best means for overcoming this inhibition in brain tumors is yet to be understood. In this project, we designed and developed a panel of artificial receptors that can be expressed on CAR T cells to convert the inhibitory signal into a T-cell activating signal. These artificial PD-1 receptors or checkpoint reversal receptors (CPR) can be expressed on T cells along with a HER2-specific CAR using a single gene. We have carried out a series of laboratory experiments and animal studies using mouse models of human GBM to assess the antitumor function of the candidate CAR/CPR T cells. Compiling the results from these studies, we have identified the top CAR/CPR T-cell product that shows significantly superior antitumor activity over the HER2-CAR T-cell that we previously tested in patients with GBM. We are currently developing a clinical grade CAR/CPR T-cell product that can be tested for safety and efficacy in patients with GBM in a phase I clinical trial.
