Fibrin-CAR-T cells therapies to enhance efficacy in glioblastoma treatments

Abstract This proposal addresses limitations in the delivery of therapies to treat glioblastoma (GBM), a lethal and hard- to-treat cancer of the brain. We propose regional delivery of chimeric antigen receptor (CAR) T cells for GBM that bypasses the blood-brain barrier. Failure to sustain the delivery to address T cell exhaustion and proliferation while considering the GBM-tumor microenvironment (TME) adversely affects therapeutic antitumor efficacy in both animal models and humans. We develop physiological biomaterial a fibrin-based hydrogel (FBH) encapsulating CAR-T cells (F-CAR-T) that can afford treatment combinations to close these critical gaps and lack of knowledge for translation of the CAR-T cell therapy. The MOSAIC Postdoctoral Career Transition Award proposal demonstrates a resurgence in delivering a cellular therapy approach to treat GBM by understanding biomaterial and immune mechanisms to improve comprehensive tumor targets. Specific Aims are: 1). Increase persistence of CAR-T cells and anti-tumor efficacy by co-delivery of cytokines with F-CAR-T in post-resection GBM model. 2) Determine whether co-delivery of F-CAR-T with TLR 7,8 agonist targeting TAMs can improve outcomes in partial tumor resection GBM model. 3). Determine whether our innovative F-CAR-T can be additive when employed in combination with the approved anti-angiogenic drug, Avastin. This study is relevant to the agency as delivering effective therapies offers fundamental knowledge of relevant approaches to reduce the GBM burden in humans. Dr. Ogunnaike's career goals are to launch a robust and successful research program by receiving a tenure-earning faculty position in an academic institution leading multi-disciplinary research to push the boundaries of biomaterial delivery systems and physiology, from cells to behavior, while mentoring the next generation of cancer researchers in the field of nanobiotechnology and immune engineering. Her career development plans are to gain knowledge and skills in the areas of CAR-T cell therapy, GBM TME, drug delivery and biomaterials. This training is essential for the future studies of advanced delivery and targeted therapy in the candidate's lab. Dr. Ogunnaike's training will include honing management, technical writing, and effective research oral communication skills. Her mentors are Dr. Alexander Kabanov, an expert in drug delivery, and Dr. Gianpietro Dotti, an expert in oncology and CAR-T cell therapy. Her training will be enhanced by collaboration with Dr. Marina Sokolsky, a director of the Translational Nanoformulations Research with expertise in drug delivery and gel carriers; Dr. Shawn Hingtgen, an expert in GBM cell therapy and Dr. Timothy Gershon a clinician scientist both having expertise in GBM animal models. The mentored research will occur within the UNC Eschelman School of Pharmacy (Dr. Kabanov), UNC School of Medicine (Dr. Dotti), and the UNC Lineberger Comprehensive Cancer Center where all mentors and collaborates are affiliated.