Project Details
Description
Project Summary
Glioblastoma (GBM) prognosis remains dismal with a median survival of 16-18 months despite the use of
multimodality treatment. Immunotherapy attempts have been unsuccessful in GBM treatment, including
negative phase III trials of immune checkpoint inhibitors and vaccines. Based on strong preclinical data, we
hypothesize that we can develop an effective immunotherapy approach against GBM by employing an
immunostimulatory measles virus strain (MV-s-NAP) expressing the Helicobacter Pylori neutrophil-activating
protein (NAP), a toll-like receptor 2 agonist. We also hypothesize that MV-s-NAP induced changes in the tumor
microenvironment, resulting from immunogenic cell death, can increase efficacy and lead in synergy when
combined with immune checkpoint inhibitors. We propose to further enhance the efficacy of this approach by
blocking the inhibitory effect of IDO upregulation. We also propose to optimize viral replication in glioblastoma
by blocking the interferon response pathway, a known mechanism of mammalian cell resistance to oncolytic
viruses, with JAK inhibitors. This project has three specific aims: In specific aim 1, we plan to evaluate the
efficacy, optimal sequence and mechanism of action of MV-s-NAP virotherapy in conjunction with antibody
blockade of the PD-1/PD-L1 axis and IDO inhibitors in immunocompetent GBM models, including GL261,
CT2A, as well as genetically engineered models of spontaneous gliomagenesis. In specific aim 2 we will
evaluate the impact of modulating expression of interferon stimulated genes on the efficacy of MV-s-NAP
virotherapy and immunovirotherapy by inhibiting the interferon response pathway, which has been shown to
decrease viral permissiveness and replication. In specific aim 3 we will test the safety of the optimal efficacy
approach identified in specific aims 1 and 2 by conducting toxicology and biodistribution studies in measles
replication permissive Ifnarko CD46 Ge mice (an FDA approved model of measles virus replication) in order to
determine the safe dose of the combination prior to clinical translation. Safety of the recommended human
dose will be further confirmed in a second primate (Rhesus macaques) model. Overall, this work will introduce
an innovative multipronged immunovirotherapy approach in the treatment of glioblastoma that has the potential
to overcome the lack of efficacy observed with other strategies.
Status | Active |
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Effective start/end date | 3/1/21 → 2/28/25 |
Funding
- National Cancer Institute: $456,968.00
- National Cancer Institute: $390,569.00
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