Engineered Glioblastoma-specific T cells using Immunostimulatory Photothermal Nanoparticles

PROJECT SUMMARY The goal of this STTR Phase II application is to advance the development and translation of IB-T cells, a personalized and multi-targeted autologous adoptive T cell therapy (ATCT) for glioblastoma (GBM). This project is a partnership between ImmunoBlue (PI: Dr. Elizabeth Sweeney) and George Washington University (GW) (PI: Dr. Rohan Fernandes). GBM is the most common primary brain tumor, and is associated with a dismal prognosis and five-year relative survival of 7.1%. In response to this need, we have developed photothermally activated IB-T cells, a personalized ATCT targeting multiple tumor-derived antigens in GBM. IB- T cells are generated by administering Prussian blue nanoparticle-mediated photothermal therapy (PTT) to patient tumor cells excised during surgery. PTT elicits immunogenic cell death (ICD) and facilitates the release of tumor antigens and immune adjuvants. These unique tumor antigens are used to expand personalized tumor-specific IB-T cells in the presence of autologous dendritic cells (DCs). For our Phase 1 clinical trial, we envision administering IB-T cells as an adjuvant therapy directly into the tumor bed through an Ommaya reservoir after standard-of-care surgery. In our STTR Phase I studies, we established the feasibility and efficacy of developing autologous GBM-specific IB-T cells with our PTT platform using peripheral blood and GBM tumor samples from patients. Specifically, we illustrated that PTT-treated GBM cells facilitate the generation of potent and personalized GBM-specific IB-T cells in an antigen-agnostic manner (n=6 patients). These patient-specific IB-T cells exhibited functional specificity toward the tumor cells, as measured by IFN-ɣ ELISpot and cytotoxicity assays in vitro. In contrast, non-specific T cells from the same patients did not respond to autologous tumor cells. In this STTR Phase II study, we seek to address scale-up, manufacturing, and safety considerations to ensure reproducibility, low toxicity profiles, and GMP compatibility of IB-T cells, as we prepare to submit an IND application with the FDA. In Aim 1, we seek to develop GMP manufacturing protocols and perform engineering runs for IB-T cell products (n=4). We will initiate technology transfer with the GW GMP facility to translate our IB-T manufacturing protocol into GMP compliance, and establish a quality control program that defines the critical quality attributes (CQAs) of IB-T cells and release testing criteria. In Aim 2, we will test the efficacy of GMP-manufactured IB-T cell products in orthotopic PDX models generated in NSG mice in vivo. Next, we will perform IND-enabling studies, including in vitro off-target and autoreactivity testing with autologous products, and in vivo toxicity and biodistribution testing using syngeneic murine models (i.e. GL261 and SB28). Together, ImmunoBlue and GW have the personnel and resources to undertake the studies proposed in this project, including experts in neuro-oncology, cell therapies, and immunoengineering, and an in-house GMP facility available at GW. Importantly, this project will take ImmunoBlue’s IB-T cell therapy from preclinical validation to clinical readiness, setting the stage for a Phase 1 clinical trial for GBM patients.