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Adoptive immunotherapy has demonstrated unprecedented success in the treatment of pediatric leukemia. Extending its therapeutic potential to other pediatric malignancies such as glioblastoma (GBM) has proved challenging. In this therapy, T cells are isolated from a patient, expanded outside of the body, and genetically modified prior to reinfusion. The ability of these T cells to recognize and eliminate cancer cells is improved by expressing a protein (CAR) on the T cell surface. An important challenge is to minimize the manipulation of patients' T cells outside the body. Prolonged culture compromises their efficacy. Dr. Ghassemi developed approaches to generate CAR T cells in 1 day. These cells have increased potency. She is combining this recent development with a metabolic strategy to overcome the metabolic nature of tumor environment. This synthetic advancement combined with the production of CAR T cells in 1 day will lead to superior CAR T cells for cellular immunotherapies against pediatric GBM.

This grant is funded by and named for the Be Brooks Brave Fund. Despite his diagnosis at age 5 with inoperable brain and spinal tumors, Brooks taught so many people what life is truly about--love. He was BRAVE beyond his years with an inspiring “faith over fear” attitude. This Hero Fund hopes to raise money for high-grade glioma research so no other family will hear the words, “there is no cure”.

Adoptive immunotherapy has demonstrated unprecedented clinical success in the treatment of leukemia. In this therapy, T cells are isolated from a patient, expanded outside of the body, and genetically modified prior to reinfusion. The ability of these T cells to recognize and eliminate cancer cells is improved by expressing a protein (CAR) on the T cell surface. This protein increases "specificity," the ability to recognize cancer cells, and "function," the ability to destroy those cancer cells. An important challenge in cellular immunotherapy is to minimize the manipulation of patients' T cells outside the body. Prolonged culture protocols trigger functional exhaustion and compromises their efficacy upon return to the body. A critical issue involves the pre-requisite "activation" step necessary for CAR expression on the cell surface of T cells. By optimizing culture conditions, Dr. Ghassemi developed approaches to express CAR in dormant T cells without the need for activation. Importantly, her preliminary findings show that elimination of this activation step retains effector function and potency of CAR T cells in models of the pediatric cancer ALL. This project is providing insight into the regulatory components influencing CAR expression in dormant T cells which will lead to superior CAR T cells for cellular immunotherapies against ALL.

This grant is supported by TEAM ABBY Gives, a St. Baldrick's Hero Fund. Abby was diagnosed with Pre-B ALL when she was almost five years old. She had a successful bone marrow transplant, but battle battled graft vs. host disease (GVHD) for years. Abby and her treatment team worked hard over many years to keep the GVHD in check. Sadly, Abby passed away on October 19, 2021. This fund unites the incredible support of family and friends in Abby's memory and inspires others to join the fight for cures and better treatments.