Potent and Affordable GD2-Specific CAR T Cell Therapy for Glioblastoma Treatment Using Biomaterials

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

PROJECT SUMMARY Glioblastoma is the most common primary brain malignancy in adults yet has no cure. Patients typically only live 12-15 months after treatment, with a five-year survival rate of less than 10%. Despite the poor patient outcomes, only three new treatments have been approved for glioblastoma since 2005: temozolomide, bevacizumab, and tumor-treating fields. The most common treatment method is maximal surgical resection followed by radiotherapy or chemotherapy, but the highly progressive and recurrent nature of the disease causes treatment to be ineffective. Chimeric antigen receptor (CAR) T cell therapy has emerged as a successful anti-cancer immunotherapy with significant impact in treating blood cancers. There have been six FDA approved CAR T cells therapies since 2017, demonstrating its clinical relevance. Unfortunately, typical CAR T cell production is a complex and expensive process involving harvesting the patient’s blood, isolating the T cells, transferring the CAR gene, extensive ex vivo expansion, and finally infusion of the expanded CAR T cells back into the patient. This process costs around $500,000 per dose and can take over 20 days to complete. It is often used as a last resort, causing many patients to succumb to their disease before receiving treatment. In addition, the lengthy ex vivo expansion deteriorates T cell quality as it encourages T cell differentiation. It has been clinically shown that having less-differentiated naïve/stem-like and central memory phenotypes after infusion is directly related to patient outcomes due to the enhanced persistence of these phenotypes compared to effector phenotypes. The goal of this project is to reduce the CAR T cell manufacturing time to three days and improve the quality and potency of CAR T cells by using biomaterials to manufacture CAR T cells in vivo. These scaffolds will be used to manufacture CAR T cells against GD2, a tumor-associated antigen overexpressed on glioma cells but limitedly expressed on adjacent healthy cells. Limiting ex vivo manufacturing will reduce CAR T cell differentiation for enhanced CAR T cell quality and persistence to improve therapeutic efficacy. For Aim 1, in vitro studies will determine how CAR T cells are released from the scaffold over time and the phenotype of released cells. In vitro coculture experiments with scaffold-produced CAR T cells and glioma cells will be performed to evaluate tumor killing ability and secretion of proinflammatory cytokines. For Aim 2, an in vivo patient-derived orthotopic xenograft model will be used to determine anti-tumor efficacy and survival in mice treated with biomaterial- generated CAR T cells. In vivo CAR T cell phenotype and persistence will be evaluated in the blood, brain, bone marrow, and spleen. This project will have a profound impact on glioblastoma treatment by demonstrating the potential for biomaterials to provide sustained local delivery of less-differentiated CAR T cells, show enhanced efficacy, and prevent disease relapse, which are highly important factors for clinical success in GBM patients.