Abstract Despite advancements in molecular characterization of pediatric high-grade glioma (pHGG), treatment options remain limited, and the current standard of care is rarely effective. Cellular therapies have been promising for other cancers but have remained a challenge for high-grade glioma. The paucity of good targets on the cell surface of pHGG remains a major bottleneck for developing an effective CAR-T therapy. To address these challenges, we are developing Peptide-Centric Chimeric Antigen Receptors (PC-CARs) for pHGG and pediatric low-grade glioma (pLGG). Unlike traditional CARs that target surface proteins, PC-CARs focus on intracellular tumor antigens/peptides presented on the cell surface by Human Leucocyte Antigen receptors, offering a unique and potentially transformative approach to glioma immunotherapy. In an immunopeptidomics campaign, we identified over 108k unique peptides presented by HLA-I receptors of pHGG and pLGG. Because we identified a large number of potential peptides to target, we have the luxury to be highly selective and only retain those peptides derived from essential or lineage-defining genes, reducing the likelihood of antigen escape. Prioritization of candidate genes/peptides, which focuses on the peptide binding affinity, parent gene properties (oncofetal, lineage defining and/or essential gene), and uniform expression within and across tumors, is ongoing. Several peptides have passed our selection criteria, and we are currently performing scFv panning experiments to design binders. Subsequently, we will develop and de-risk PC-CARs through rigorous in vitro and in vivo testing to eliminate cross-reactivity with normal cells. Extensive in vitro and in vivo experiments will evaluate tumor clearance, persistence of CAR-T cells, and safety.
Li et al. (Tue,) studied this question.