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Principal Investigator: Brian Lim Hoh
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $75,099
Funding agency: National Institute of Neurological Disorders and Stroke
Diffuse Midline Glioma (DMG) is an inoperable pediatric brain tumor with no good 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). They can provide near
immediate immune induction against inciting malignancies. RNA-NPs can thus be harnessed as an
effective therapy for patients with DIPG and other refractory malignancies. In addition, DIPG has a
highly conserved H3K27M mutation that serves as an excellent target for these therapies.
Based on the above, we propose exploring the immunogenicity of RNA-NPs targeting the DIPG
H3K27M mutation, as well as the feasibility, safety, and anti-tumor activity of tumor loaded RNA-NP
vaccines in animal models. These RNA NPs have shown survival benefit in our preclinical murine model
of DMG. Among these animals with significant survival benefit, there is development of hydrocephalus,
which is thought to be secondary to increased lesion size secondary to an immunotherapeutic response
during treatment. In our clinical trials investigating RNA NPs as a treatment for canine glioma in adult
dogs, we saw a similar effect in MRI imaging of animals that became long-term survivors. Following
detailed analysis of these lesions in mouse, canine and human patients during RNA-NP therapy, there
appears to be features of both reactive gliosis and traditional pseudoprogression (immune infiltration),
suggesting a new radiographic diagnosis I have named paraprogression. I hypothesize that
paraprogression is a novel radiographic entity characterized by reactive gliosis and increased lesion size
in therapeutic responders. In this study, I aim to visualize paraprogression using advanced MRI
techniques, elucidate the mechanism behind the increase in lesion size, and combat this effect without
compromising our promising survival benefit conferred by RNA NP vaccine in our preclinical DMG
model.
Terms: <21+ years old><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Animals><Antigens><Cancers><Canine Species><Canis familiaris><Childhood><Childhood Brain Neoplasm><Childhood Brain Tumor><Clinical Trials><DIPG><Development><Diagnosis><Diffuse intrinsic pontine glioma><Disease><Disorder><Dogs><Dogs Mammals><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Gliosis><H3 K27M mutant><H3 K27M mutation><H3K27M mutant><H3K27M mutation><Health><Human><Hydrocephalus><Hydrocephaly><Immune><Immune infiltrates><Immunes><Immunotherapeutic agent><Knowledge><Lesion><Life><Long-Term Survivors><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Neoplasms><Malignant Tumor><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Mice><Mice Mammals><Modality><Modeling><Modern Man><Murine><Mus><NMR Imaging><NMR Tomography><Names><Neuroglial Neoplasm><Neuroglial Tumor><Non-Polyadenylated RNA><Nuclear Magnetic Resonance Imaging><Patients><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Radiography><Refractory><Ribonucleic Acid><Roentgenography><Safety><Secondary to><Techniques><Therapeutic><Tumor Burden><Tumor Load><Tumor-Derived><Vaccines><Visualization><Zeugmatography><adulthood><animal imaging><canine><combat><developmental><diffuse midline glioma><disability><domestic dog><effective therapy><effective treatment><glial-derived tumor><hydrocephalic><immune cell infiltrate><immune drugs><immune-based therapeutics><immunogen><immunogenicity><immunologic therapeutics><immunotherapeutics><immunotherapy agent><lipid based nanoparticle><lipid nanoparticle><longterm survivors><mRNA vaccine><mRNA-based vaccine><malignancy><model of animal><mouse model><murine model><name><named><naming><nano particle><nano-sized particle><nanoparticle><nanoparticle therapy><nanosized particle><neoplasm/cancer><neuroglia neoplasm><neuroglia tumor><novel><pediatric><pediatric brain neoplasm><pediatric brain tumor><pre-clinical><preclinical><radiologic imaging><radiological imaging><response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic nanoparticles><tumor>