Glioblastoma multiforme (GBM) represents the most common primary malignant tumor of the adult central nervous system. The median survival after surgical intervention alone is approximately six months and the addition of radio-/chemotherapy can extend this time up to fourteen months. Consequently, efforts aimed at developing new therapies have focused on treatment strategies that target the tumor environment but spare normal and healthy surrounding brain cells.
Oncolytic adenoviral therapy is a novel modality of anti-cancer treatment. Our group has created the oncolytic vector CRAd-Survivin-pk7 (CRAd-S-pk7) for the treatment of malignant gliomas. For transcriptional targeting in gliomas, we incorporated the survivin promoter upstream from viral gene E1A. The survivin promoter is highly active in gliomas but remains silent in the surrounding brain parenchyma. To enhance viral transduction into glioma cells, the capsid of this vector was modified to bind heparan sulfate proteoglycans expressed in these tumors.
In our extensive preclinical studies, CRAd-S-pk7 exhibits potent anti-tumoral activity in mice bearing intracranial human glioma xenografts, including the highly aggressive CD133+ glioma stem cell model. In addition, we have recently shown that this virus elicits a synergistic therapeutic effect when combined with low dose radiation and with the chemotherapeutic agent temozolomide, two therapies that constitute the standard of care for patients with malignant glioma.
Since one of the major limitations of virotherapy is poor spread following injection, we have recently shown that mesenchymal stem cells (MSC) can more effectively migrate and deliver an oncolytic adenovirus to intracranial glioma than local injection of the virus alone. This form of carrier mediated delivery leads to enhanced viral replication in the tumor and a much more potent anti-tumor response than local injection of the virus alone.
Moreover, our studies further suggest that MSC suppresses the anti-adenoviral immune response, further enhancing the efficacy of oncolytic virotherapy. In order to translate our work into the clinical setting, we now propose to develop a clinical trial in which this novel virus will be delivered via MSCs.
To achieve this goal, we would like to utilize Alliance for Cancer Gene Therapy funding to complete the following aims:
- Aim 1: Validate the therapeutic efficacy of CRAd-S-pk7 loaded MSCs in vitro and in animal models of glioma.
- Aim 2: Evaluate the therapeutic efficacy and safety monitoring with CRAd-S-pk7 loaded MSCs in the presence of temozolomide-based chemotherapy and radiotherapy.
- Aim 3: Determine the migration, engraftment, and long-term fate of CRAd-S-pk7 loaded MSCs in vitro and in animal models of glioma with MRI.
- Aim 4: Perform a toxicology/biodistribution study with MSC-loaded cGMP-grade clinical lot virus.
- Aim 5: Conduct RAC and FDA meetings and assemble documents for filing an IND application for mesenchymal stem cell based.