Encouraging clinical experience with chimeric antigen receptor (CAR) T cells supports the notion that even immune-privileged sites such as the brain may be amenable to CAR T therapy. In the context of hematologic B cell malignancies, CD19-CARs have been shown to accumulate in the cerebrospinal fluid (CSF) and reduce the incidence of metastatic disease in the central nervous system. However, treatment of solid tumors, including brain tumors, has proven quite challenging due to heterogeneous antigen expression, suboptimal trafficking, and immunosuppressive networks in the tumor microenvironment that limit CAR T cell function and persistence. This presentation will describe our efforts to overcome these challenges for the treatment of glioblastoma (GBM), one of the most common and aggressive primary malignant brain tumors. Tumor antigen selection is a key challenge for CAR T therapy of brain tumors, as on-target/off-tumor toxicities could be life-threatening. Our preclinical studies demonstrate that a glioma-associated protein, interleukin 13 receptor alpha 2 (IL13Rα2), is an attractive CAR T cell target for glioblastoma in part because this tumor-restricted antigen is expressed by the majority of GBM. Initial clinical findings demonstrate that local delivery of IL13Rα2-CAR T cells is feasible and safe, with evidence for clinical activity in patients. In addition, as part of our on-going efforts to expand the repertoire of immunologic targets for GBM, we have optimized a HER2-CAR and developed a novel toxin-based CAR harnessing the selective GBM-binding properties of chlorotoxin (CLTX). To reduce the potential for tumor antigen escape, we are exploring approaches that leverage multiple antigens, including combining CAR T cells specific to different antigens and developing tandem CARs. Another challenge is achieving efficient tumor trafficking and infiltration of CAR T cells to brain tumors. While different routes of delivery present advantages and disadvantages, our preclinical studies using several tumor models suggest that locoregional delivery, into either the tumor or cerebral spinal fluid (CSF), is more effective than systemic delivery for treatment of brain tumors. These studies underlie our clinical approach of infusing T cells into both the resected tumor cavity and CSF. Indeed, we have demonstrated that CAR T cells administered into the CSF induced a complete response in a patient with recurrent multifocal GBM, including metastatic lesions in the spine.Additional efforts are addressing the highly immunosuppressive GBM microenvironment that limits the effectiveness of adoptively transferred T cells. Our studies highlight the impact of the PD-1/PDL-1 immune checkpoint axis in reducing the antitumor activity of CAR T cells, an inhibition that can be overcome by anti-PD-1 checkpoint blockade. In another approach designed to interrogate the interplay between the tumor microenvironment (TME), host immune system, and CAR T cells, we have established a syngeneic mouse model recapitulating the invasive nature of GBM. These studies are elucidating the reciprocal interactions of CAR T cells, the immune landscape, and the inflammatory TME. In summary, this presentation will highlight on-going studies focusing on the biology of GBM, its microenvironment, and strategies to enhance CAR T cell approaches to more effectively treat brain tumors.
Citation Format: Darya Alizadeh, Dongrui Wang, Renate Starr, Brenda Aguilar, Vanessa D. Jonsson , Saul J. Priceman, Michael E. Barish, Behnam Badie, Stephen J. Forman, Christine E. Brown. Advancing CAR T cell therapy for the treatment of brain tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA15.