Abstract 6328: An off-the-shelf Twin BiTE combination therapy controls heterogenous glioblastoma and shapes immune response

Abstract

Abstract Glioblastoma (GBM) is the most common primary brain tumor in adults, characterized by a median survival of 12-14 months with less than 10% of patients surviving at least 2 years from diagnosis. The discovery of tumor-associated antigens (TAAs) has permitted development of a new array of therapeutic strategies that selectively target GBM and spare normal cells of the CNS. In this study we used an alternative off-the-shelf approach to activate the immune system and direct it against the tumor, taking into account antigen heterogeneity and TME immune suppression without the need of engineering the patient’s immune cells. We generated TAA-targeting Bispecific T-cell Engagers (BiTEs) and engineered adult stem cells to secrete twin BiTEs (T-BiTE-SC). The approach was tested in combination with in naïve T cells on established and primary patient-derived cell lines expressing various levels of the target antigens. Moreover, to further support the therapeutic action of T cells, and combat immune-suppressive microenvironment and exhaustion, we combined our T-BiTE SC with an immune-stimulating cytokine. We show the efficacy of the individual BiTEs against different primary and established tumor cell lines. Moreover, the T-BiTE-SC, significantly controlled the growth of a tumor expressing heterogeneous levels of the targeted antigens. The immune stimulation reduced T cell exhaustion and consolidated a Th1 phenotype. Altogether our study demonstrated the feasibility and efficacy of an off-the-shelf immunotherapy, based on BiTEs simultaneously targeting tumor heterogeneity without the need for direct engineering of the immune cells. Citation Format: Filippo Rossignoli, Paulo Borges, Rebecca Lumia, Khalid Shah. An off-the-shelf Twin BiTE combination therapy controls heterogenous glioblastoma and shapes immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6328.