Defining Antigen-Dependent and Antigen-Independent Mechanisms for EGFRviii-Expressing Tumor Escape From Therapy

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PROJECT SUMMARY/ABSTRACT Glioma is a form of cancer that occurs in glial cells in the brain and central nervous system. Glioma has very poor prognoses in children and adults due to lack of, or ineffective, available therapies. Commonly used available therapies for gliomas and other brain cancers include surgery, radiation therapy, and chemotherapy. However, these therapies only prolong survival and rarely completely eliminate the tumor. One potential therapy for glioma that has been tested in clinical trials is CAR T cell therapy targeting epidermal growth factor variant 3 (EGFRviii). Similar CAR T cell therapies have proven effective and are approved in blood cancers, including diffuse large B- cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), and multiple myeloma. However, CAR T cells have proven less effective in glioma and other solid tumors and certain tumor cells ‘escape’ from CAR T cell therapy, and develop resistance to CAR T cells. Potential tumor cell intrinsic factors that may lead to escape include lack of homogeneous antigen expression, mutations in the EGFRviii target antigen itself, and mutations in other genes leading to resistance to killing. In this grant, I propose to study genomic and transcriptomic mechanisms for tumors that escape from CAR T cell therapy, and hypothesize that tumors that escape from CAR T therapy acquire distinct targetable mutational loads through the activation of APOBEC cytidine deaminase enzymes. I propose to generate tumors that escape from and develop resistance to sub-optimal T cell therapies both in vivo and in vitro, and characterize the mutational load and transcriptional changes that occur upon escape from CAR therapy. Depending on genomic and transcriptomic changes that occur, I will propose and test either a chemotherapeutic combination targeting mutational pathways such as APOBEC, or an immunotherapeutic combination therapy targeting neoepitopes in mice. If successful, the overall impact of this research will be the identification of mutations and changes in gene expression that are the result of CAR T cell therapy in escaped variants, and a potential combination therapy to target CAR escaped variants.