Brain tumors are the leading cause of death from childhood cancer, surpassing leukemias. Current therapies including radiation, chemotherapy and/or surgery are unable to cure the disease and are associated with serious adverse effects and long-term impairments. Immunotherapy using chimeric antigen receptor (CAR) T cells offers a potentially safer and more effective alternative with engineered T lymphocytes redirected to harness a primary immune response against tumor-specific antigens. Early clinical studies demonstrated safety of CAR T cell therapy for brain tumors; yet only limited benefits were observed. Lack of efficacy is most likely multifactorial and include: (i) the suppressive tumor immune microenvironment (TIME) consisting of immune cells and mediators directly suppressing CAR T cell efficacy; (ii) inherent CAR T cell limitations due to the induction of transcriptional and epigenetic alterations that mediate exhaustion and limited persistence; (iii) physical and biological barriers for CAR T cell homing, trafficking, and penetration of the tumor; and (iv) resistance due to tumor antigen heterogeneity and downregulation. Therefore, the overarching goal of the Haydar Lab is to directly address these limitations in order to engineer a potent CAR T cell therapy for pediatric brain tumors. Our work is focused on investigating novel designs, additional genetic modifications, or combination therapies that will improve CAR T cells antitumor effects.
- Using immune competent CAR T cell models to interrogate interactions with the TIME for the identification of rational combination therapies.
- Using novel engineering tools to develop unique CAR designs for optimal efficacy in different subtypes of pediatric brain tumors.
- Developing next-generation CAR T cell products based on understanding intrinsic CAR T cell programs that control effector functions and long-term memory formation.
- Proteogenomic discovery of tumor-specific antigens that could serve as new targets for T cell immunotherapy.
- Exploring novel strategies to mitigate the TIME for enhanced efficacy of anti-brain CAR T cells.