ABSTRACT
Glioblastoma (GBM) is the most common primary tumor of the adult central nervous system, with poor prognosis despite standard treatment options (Alsajjan & Mason, 2023). Immunotherapies, including T cell engagers (TCEs) and Chimeric Antigen Receptor (CAR) T cells, hold promise for treating solid tumors like GBM. However, these approaches are often limited by a shortage of specific, highly recurrent tumor-associated targets (Flugel et al., 2023).
We previously applied a proteogenomic pipeline to analyze transposable element expression in GBM patients, combining single-cell and bulk RNA sequencing (RNA-seq) from tumors and healthy-tissue cohorts, along with immunopeptidomic data (Bonte et al., 2022). This led to the identification of a novel peptide target, MNO-P3, derived from a long terminal repeat (LTR) and presented on HLA-A3. MNO-P3 was found to be both GBM-specific and highly recurrent among patients.
We here show the development of targeted immunotherapies against MNO-P3, specifically TCEs and CAR T cells. Through phage display screening, we identified highly specific single-chain variable fragments (scFvs) that recognize MNO-P3 presented on HLA-A3. These scFvs demonstrated strong cytotoxic activity against MNO-P3-positive/HLA-A3-positive GBM cell lines, with minimal cross-reactivity, when used as TCEs or CARs. These candidates are currently undergoing extended preclinical evaluation, with a plan to initiate GBM patient treatments in 2026.
Overall, our proteogenomic strategy, which mines tumor-specific transposable element expression, has yielded a novel, highly specific GBM pMHC target. This target underpins the ongoing development of next-generation immunotherapies at Mnemo for improved cancer treatment.