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Hector Mendez-Gomez, Brandon Wummer, Adam Grippin, Frances Weidert, Jianping Huang, Loic Deleyrolle, Duane Mitchell, Elias Sayour, IMMU-32. RNA-NANOPARTICLE VACCINES MEDIATE T CELL TRAFFICKING NECESSARY FOR BBB PASSAGE AND ANTI-GLIOMA IMMUNE RESPONSE, Neuro-Oncology, Volume 21, Issue Supplement_6, November 2019, Pages vi125–vi126, https://doi.org/10.1093/neuonc/noz175.524
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Abstract
The blood-brain barrier (BBB) remains a potent obstacle for development of new therapies against glioblastoma (GBM). While activated T cells can cross the BBB, immunotherapy has yet to be fully unlocked for malignant brain tumors due their heterogeneity and immunosuppressive microenvironments. To overcome these challenges, our group has developed a novel treatment platform, which leverages the use of a clinically translatable nanoparticles (NPs) combined with personalized tumor derived mRNA to peripherally activate T cells against a heterogenous source of tumor antigens and reprogram the intratumoral milieu into an immune activated state.
We sought to assess if RNA-NPs could activate systemic/intratumoral dendritic cells (DCs) and mediate a peripheral T cell response that could penetrate the GBM microenvironment.
We uncovered that RNA-NPs elicit potent innate immunomodulating effects through release of interferon-α (IFN-α) from plasmacytoid DCs (pDCs). After only a single RNA-NP vaccine, the bulk of systemic and intratumoral DCs in mice display an activated phenotype; DCs, harvested from intracranial tumors, elicit expansion of antigen specific T cell immunity. Tumor-specific RNA-NPs elicited enhanced survival outcomes in immunocompetent animals bearing NF-1/p53 mutant gliomas with increased intratumoral memory CD8+T-cells. Unlike immune checkpoint blockade (anti-PD-L1 mAbs), we found that RNA-NPs increase LFA-1 on peripheral CD8 splenocytes, which is necessary for activated T cell passage across the BBB. RNA-NPs also increased CCR2 on peripheral CD8 cells, which was dependent on IFN-α/β, as the percentage of CCR2+CD8+ splenocytes and anti-tumor activity (mediated by RNA-NPs) was abrogated in animals receiving concomitant type I IFN receptor (IFNAR1) mAbs.
Since LFA-1 is important for T cell trafficking across the BBB and CCR2 may promote chemotaxis to the brain (as GBMs are known to secrete CCL2), RNA-NPs may offer a new treatment modality and immunologic mechanism for unlocking peripheral T cell immunity against malignant gliomas.
- phenotype
- immunosuppressive agents
- immune response
- brain tumors
- glioblastoma
- heterogeneity
- antigens
- blood-brain barrier
- cd8-positive t-lymphocytes
- chemotaxis
- dendritic cells
- glioma
- objective (goal)
- immunity
- immunocompetence
- immunotherapy
- interferons
- lymphocyte function-associated antigen-1
- monocyte chemoattractant protein-1
- neurofibromatosis 1
- interferon receptor
- rna, messenger
- t-lymphocytes
- vaccines
- brain
- memory
- mice
- neoplasms
- rna
- tumor antigens
- human leukocyte interferon
- glioma, malignant
- immunology
- nanoparticles
- cell cycle checkpoint