Immunotherapeutic paraprogression defines a novel entity in primary high-grade glioma

Introduction: Diffuse Midline Glioma (DMG) is an inoperable pediatric brain tumor without sufficient treatment options. Our group has developed a novel treatment modality for this disease and others, using mRNA vaccines consisting of tumor derived antigens packed into a unique lipid-nanoparticle (NP). These RNA NPs have shown survival benefit in our preclinical murine model of DMG. Among these long-term survivors, there is development of hydrocephalus, thought to be secondary to increased lesion size due to an immunotherapeutic response. Conventional MRI fails to distinguish between residual tumor tissue, treatment effect, and the molecular landscape of the tumor microenvironment. Intermolecular Zero Quantum Coherence (iZQC) MRI can reveal subtle alterations in tissue composition to provide insight into the complex interplay of molecules within biological systems.

Methods: We have treated mice, canines, and human patients with primary brain tumors to define immunotherapeutic local treatment response. We treated our neonatally implanted K2 DMG model with RNA NPs generated from total-tumor mRNA beginning day 30 and used iZQC MRI to visualize tumors and treatment effect.

Results: In our clinical trials investigating RNA NPs as a treatment for canine glioma, we visualized radiographically enlarging tumors of animals that became long-term survivors. Following detailed analysis of these lesions in canine and human high-grade glioma patients receiving RNA-NP therapy, there appears to be features of both reactive gliosis and traditional pseudoprogression (immune infiltration), suggesting a new radiographic diagnosis, thus named paraprogression. In mice bearing DMG, RNA NPs were found to be immunogenic and efficacious, resulting in a group of long-term survivors, despite the development of hydrocephalus. iZQC MRI allowed for visualization of tumor and paraprogression.

Conclusion : These results are rapidly translatable and applicable to aid clinical decision making in patients with brain tumors treated with immunotherapy. Future studies will target treatment of paraprogression without compromising benefit of RNA NP therapy.