Abstract 1418: Priming of the glioblastoma tumour microenvironment via copper chelation to enhance the efficacy of immunotherapies
Authors: Shai-Hee Tyler , Jue Toni Rose , Cazzoli Riccardo , Rouaen Jourdin R. , Michniewicz Filip , Bell Jessica , Gargett Tessa , Brown Michael P. , Vittorio Orazio 
Published: March 2024

Glioblastoma, a highly aggressive brain tumor with a dismal prognosis necessitates novel therapeutic approaches as current standard treatments yield limited success. Despite the transformative impact of immune checkpoint blockade in various malignancies, its efficacy in glioblastoma remains elusive. Similarly, chimeric antigen receptor T (CAR-T) cell therapy, while successful in hematological malignancies, faces challenges in solid tumors. This study addresses the immunosuppressive barriers hindering the effectiveness of immunotherapies in glioblastoma. Highlighting copper's pivotal role in glioblastoma, our research group demonstrated its elevation and influence on PD-L1 expression. Given the success of copper chelators in treating Wilson's Disease, in which neurological manifestations are alleviated following treatment, we hypothesized that copper chelation therapy could be a promising strategy for glioblastoma, especially when combined with immunotherapies. Flow cytometry analysis revealed a significant increase in the tumor-associated antigen GD2 following treatment with the copper chelator trientine (TETA), suggesting its potential synergy with GD2-targeted immunotherapies. In an immunocompetent murine glioblastoma model, combination therapy with GD2-targeted CAR-T cells and TETA effectively slowed tumor growth, demonstrating enhanced efficacy. Additionally, TETA as a monotherapy significantly improved survival compared to the control. The combination of TETA with anti-PD1 antibody therapy also exhibited promising results in inhibiting tumor growth and subsequently prolonging survival, with some mice demonstrating complete tumor regression. Importantly, TETA decreased copper levels in the brains of the mice, indicating the drug can act on the brain, a crucial therapeutic hurdle that is hampering the efficacy of novel therapies in glioblastoma. Further exploration of immune cell populations using OPAL Multiplex immunohistochemistry following TETA, anti-PD1, and GD2-targeted CAR-T cell treatments will underscore the potential of copper chelation in reshaping the tumor microenvironment. Our findings suggest that copper chelation, with agents like TETA, can be repurposed as a viable anticancer therapy when combined with immunotherapies. This study provides a compelling rationale for further pre-clinical validation, offering a potential breakthrough in the quest for effective glioblastoma treatments.

Citation Format: Tyler Shai-Hee, Toni Rose Jue, Riccardo Cazzoli, Jourdin R. Rouaen, Filip Michniewicz, Jessica Bell, Tessa Gargett, Michael P. Brown, Orazio Vittorio. Priming of the glioblastoma tumour microenvironment via copper chelation to enhance the efficacy of immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1418.