Glioblastoma is a virtually incurable brain cancer with a five-year-survival rate of only 10%.Its heartbreaking to keep telling people in clinic that we dont have a cure, said Jana Portnow, M.D., co-director of City of Hopes Brain Tumor Program. This is a tough tumor, and these patients havent benefited

from the major advances weve seen over the last 20 years to treat other cancers. Theres no effective targeted agent or immunotherapy for glioblastoma. We need to find better treatments.

Portnow and her team just received a $12 million grant from the California Institute for Regenerative Medicine (CIRM) to perform a Phase 1 clinical trial to assess an exciting new combination treatment strategy against glioblastoma.

These very invasive tumors lack clear boundaries, and most chemotherapies cannot adequately reach diffuse tumor cells in the brain. In order to overcome these treatment obstacles, this trial for patients with recurrent high-grade glioma is evaluating the strategy of packaging an oncolytic virus (a virus that can kill cancer cells without harming normal brain tissue) within tumor-homing neural stem cells. The team expects this approach will not only more effectively distribute the oncolytic virus to tumor tissue, it will protect the oncolytic virus from being destroyed by the patients immune system while making its way to tumor cells.

Karen Aboody, M.D., whose City of Hope translational research lab pioneered neural stem cell-delivered cancer therapies, collaborating with Maciej Lesniak, M.D., and David Curiel, Ph.D., on development of the trial virus product, explained how it works.

We engineered tumor-targeting neural stem cells to produce an adenovirus, which is a cold virus, but it only replicates in cells that have a high expression of a protein called survivin. Since only the cancer cells express high levels of survivin, it doesnt harm the normal tissue surrounding the tumor, she said. Just the way a cold virus infects your cells, this virus infects tumor cells and keeps replicating until it kills them by bursting them open. This virus can be especially effective on tumors that have become resistant to radiation and chemotherapy.

When the tumor cell bursts open, it releases more cancer-killing virus that spreads to neighboring tumor cells, effectively amplifying its tumor-killing effect until normal tissue is reached, and the virus ceases to further replicate. Additionally, this process of bursting open the tumor cells also exposes new tumor proteins to the immune system, potentially stimulating a secondary immune response against the tumor.

Another difficulty in treating brain tumors is that they are heterogenous, meaning they are made up of different cells resulting from various mutations in different parts of the tumor, so therapies that target only specific genetic mutations are ineffective. But the oncolytic virus is able to target all malignant cells.

However, treating cancer with a virus has its own obstacle to overcome the patients immune system, which can neutralize the virus before it can reach cancer cells. The trick was finding a way for the virus to hide from the immune system.

Enter the neural stem cell.

To avoid attack by the immune system, the virus is delivered inside a neural stem cell that is tumor-tropic, meaning it seeks out tumors and invades the cancer cells.

A major obstacle to successfully treating glioblastoma is that these tumor cells multiply so quickly and are so invasive that, even before the main tumor mass can be removed, malignant cells have already invaded other parts of the brain. The ability of the neural stem cells to migrate through normal brain tissue to seek out distant cancer cells and deliver the oncolytic virus may be the key to improving the efficacy of oncolytic viruses for treating brain tumors.

The neural stem cell serves as kind of a Trojan horse, Aboody said. The virus is concealed by the stem cell, which protects it from being neutralized by the immune system, allowing it to reach the tumor and efficiently infect the tumor cells.

'This virus can be especially effective on tumors that have become resistant to radiation and chemotherapy.'Karen Aboody, M.D.

Neural stem cells are naturally drawn to pathology in the brain, as Aboody demonstrated in a seminal study, published in PNAS in 2000. They are attracted to inflammation and chemokines secreted by the tumor cells. In fact, the more aggressive and invasive the tumor, the more stem cells are attracted to it.

In another study, published in Lancet Oncology in 2021, Aboody and her colleagues at Northwestern University showed that delivering a single dose of virus-loaded neural stem cells directly into the brain of newly diagnosed glioma patients was safe and feasible. This next CIRM-funded study will assess the safety and initial efficacy of treating participants with multiple weekly doses of this therapy,

Working with City of Hopes Center for Biomedicine & Genetics, Aboodys lab has engineered a line of virus-producing neural stem cells and banked billions of them as an off-the-shelf cancer treatment ready for clinical use.

If this Phase 1 study is successful, further manufacturing and clinical development will be supported by Calidi Biotherapeutics, a biotechnology company with which City of Hope has partnered to develop stem cell-based platforms for delivering oncolytic viruses.

Intravenous treatment for brain cancer is limited by the blood brain barrier, a kind of gatekeeper that keeps harmful substances in the blood from entering the central nervous system.

One way to bypass the blood brain barrier is to deliver the treatment directly into the brain. For this multiple treatment study, instead of making participants undergo surgery each time a dose needs to be given, a temporary catheter will be implanted into the surgical cavity after the main tumor is removed. Then the catheter, which is attached to a reservoir placed under the scalp, will be used to administer serial weekly doses of the virus-producing neural stem cells in the outpatient setting.

To reach patients across the United States, three other brain tumor centers are participating in this study. In addition to City of Hope, the clinical trial will be conducted at Northwestern University, Stanford University and Wake Forest University, all of which are National Cancer Institute-designated comprehensive cancer centers, and all of which serve diverse patient populations.

People who are at least 18 years old and have recurrent high-grade gliomas, such as glioblastoma or grade 3 astrocytomas, may be eligible to participate in this clinical trial.

For more information, contact City of Hope at 866-405-1663 and ask to speak to someone in the Brain Tumor Program or email neurosurgerymail@coh.org.

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Targeting glioblastoma with a cancer-killing virus - City of Hope