P4.028: Targeting embryonal pediatric tumors using developmental antigens in adoptive cellular immunotherapy

Background: Mutated neoantigens have shown promise as targets for cancer immunotherapy but pediatric brain tumors with notoriously low mutational burden have more limited opportunities for neoantigen directed therapies. Evidence suggests that medulloblastoma (MB) and brain stem gliomas (BSG) arise from the aberrant reactivation of post-natal developmental programming, therefore, we explored the hypothesis that early post-natal developing mouse cerebellum and brainstem expressed developmentally regulated proteins that could serve as potent tumor rejection antigens for MB and BSG, respectively.

Methods: We conducted a series of experiments in vitro and in vivo to assess the reactivity and therapeutic efficacy of brainstem and cerebellum developmental antigens as a source of renewable antigenic targets against BSG and MBs, respectively. Such experiments included ex vivo tissue culture of dendritic cells (DC), T cells, and hematopoietic stem cells (HSC). We performed RNA sequencing, ELISA, and flow cytometry. We performed in vivo survival curves in validated murine models for MB and BSG.

Results: We demonstrate that developmental antigen– specific T cells produce high levels of Th1-type cytokines that recognize distinct subtypes of MB and BSG. Furthermore, these T cells showed no cross-reactivity with normal brain tissue. Finally, use of these T cells in our adoptive cellular therapy (ACT) platform, which included DCs, T cells, and HSCs, demonstrated a survival benefit in murine orthotopic models of established MB and BSG.

Conclusion: Our studies demonstrate that RNA encoding non-mutated and organ-specific developmental antigens can serve as novel tumor rejection antigens in immunotherapy for pediatric brain cancers.