Project Details
Description
BACKGROUND AND RATIONALE
Glioblastomas (GBM) lack effective therapy. Recent advances inimmunotherapy have revitalized the enthusiasm for an immunological approach to fight cancer. However, for brain tumors, results are still unsatisfactory, pointing to the need to improve available immunotherapies. A promising strategy is oncolytic immuno-virotherapy, as oncolytic viruses(OVs) selectively kill cancer cells and can elicit additional anti-tumor immune responses. A phase I/IIa clinical trial for GBM with OV parvovirus H-1PV had with encouraging results. We aim to enhance OV-efficacy by modifying tumor cells by genetic transfer of CIITA, the major regulator of HLA class II expression, thus potentiating immunological responses. Amajor limitation in the field is the lack of clinically relevant in vivo models that allow to assess immune responses. Therefore we will develop novel, immunocompetent patient-derived organoid-coculture models of GBM and their recurrences.
AIMS
1. To develop patient-derived tumor organoids and establish co-cultures with autologous immune cells
2. To construct innovative viral vectors based on Adenoviruses (Ad) and Ad-parvovirus (Ad-PV) chimeras, combining oncolytic properties with the capacity to express CIITA.
3. To provide proof-of-principle that organoids are valid models to address immune therapeutic responses
METHODS
Fresh surgical specimen for organoid generation. Analysis of cell typecomposition and genetic/epigenetic profiling using single cell technologies. OV construction using Ad easy 1 and 2 technology. Efficacy studies inhuman GBM organoid-immune cell cocultures w/wo immune checkpoint inhibitors.
EXPECTED RESULTS AND POTENTIAL IMPACT
1. develop patient-specific, high throughput, immunocompetent ex vivo models capable to assess the efficacy of immunotherapy-based anti-GBM strategies.
2. produce proof-of-concept of enhanced anti-cancer activity of CIITA-armed oncolytic viruses that can subsequently be put to clinical test.
Glioblastomas (GBM) lack effective therapy. Recent advances inimmunotherapy have revitalized the enthusiasm for an immunological approach to fight cancer. However, for brain tumors, results are still unsatisfactory, pointing to the need to improve available immunotherapies. A promising strategy is oncolytic immuno-virotherapy, as oncolytic viruses(OVs) selectively kill cancer cells and can elicit additional anti-tumor immune responses. A phase I/IIa clinical trial for GBM with OV parvovirus H-1PV had with encouraging results. We aim to enhance OV-efficacy by modifying tumor cells by genetic transfer of CIITA, the major regulator of HLA class II expression, thus potentiating immunological responses. Amajor limitation in the field is the lack of clinically relevant in vivo models that allow to assess immune responses. Therefore we will develop novel, immunocompetent patient-derived organoid-coculture models of GBM and their recurrences.
AIMS
1. To develop patient-derived tumor organoids and establish co-cultures with autologous immune cells
2. To construct innovative viral vectors based on Adenoviruses (Ad) and Ad-parvovirus (Ad-PV) chimeras, combining oncolytic properties with the capacity to express CIITA.
3. To provide proof-of-principle that organoids are valid models to address immune therapeutic responses
METHODS
Fresh surgical specimen for organoid generation. Analysis of cell typecomposition and genetic/epigenetic profiling using single cell technologies. OV construction using Ad easy 1 and 2 technology. Efficacy studies inhuman GBM organoid-immune cell cocultures w/wo immune checkpoint inhibitors.
EXPECTED RESULTS AND POTENTIAL IMPACT
1. develop patient-specific, high throughput, immunocompetent ex vivo models capable to assess the efficacy of immunotherapy-based anti-GBM strategies.
2. produce proof-of-concept of enhanced anti-cancer activity of CIITA-armed oncolytic viruses that can subsequently be put to clinical test.
| Acronym | GBModImm |
|---|---|
| Status | Finished |
| Effective start/end date | 1/11/18 → 31/01/23 |
Funding
- FNRS - Fonds National de la Recherche Scientifique: €275,500.00
- FNRS - Fonds National de la Recherche Scientifique: €81,400.00
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