Targeting Glioblastoma

There are around 23,800 brain and nervous system cancers diagnosed each year in the United States1. The most common and also a uniformly fatal form of primary brain cancer in adults is glioblastoma multiforme (GBM)2.

Regrettably, despite decades of research, very few treatment options are available for GBM and patients diagnosed with the disease typically survive fewer than 15 months.

The current international standard-of-care is surgery, followed by radiation and chemotherapy (typically temozolomide). But not everyone responds to this treatment, and those that do almost invariably find that the tumour becomes resistant or comes back.

The difficulty in developing new treatments for brain tumours is that the central nervous system is unique in the body because it is separated from the circulatory system by the blood-brain barrier (BBB). This membrane tightly controls the traffic of immune cells, cytokines, or drugs into the brain3.

Additionally, the specialized cells that exist around a brain tumour, known as the tumour microenvironment (TME), are often immunosuppressive. This dampens the impact of any infiltrating immune cells that seek to destroy the cancer.

The good news is that a growing understanding of how the immune system functions within the brain has led to some promising early-stage trials using immunotherapy4, such as oncolytic viruses5, vaccines6 and checkpoint inhibitors7.

But in order to meaningfully tackle the disease entails overcoming this immunosuppressive TME and implementing a delivery mechanism able to bypass the BBB.

Medicenna has taken a multi-pronged approach to tackling GBM using our Empowered™ IL-4 cytokine, MDNA55.

The GBM micro-environment is supported by a robust population of immunosuppressive Myeloid Derived Suppressor Cells (MDSCs) and tumour associated macrophages (TAMs) which over-express the receptor for IL-4 (IL4R).

Crucially, in glioblastoma tumours, the IL4R is significantly increased, while being almost completely absent in normal brain tissue8.

MDNA55 is an engineered version of IL-4 that exploits this discrepancy by carrying a cell-killing payload. When MDNA55 binds to the IL4R, the entire molecule is transported into the cell where the payload is delivered, triggering cell death.

In our previous and ongoing clinical trials, this MDNA55 is locally administered after surgery by directly infusing the drug onto the tumour itself after the tumour has recurred. This delivery method means that the treatment can bypass the BBB and reduce systemic side effects.

By neutralizing MDSCs and TAMs that highly express IL-4R, MDNA55 is also able to influence the local tumour microenvironment, reducing the tumours inherent immunosuppression and potentially enhancing any follow up immunotherapy treatments.

The uniqueness of this approach allows MDNA55 to potentially treat glioblastoma with minimal side effects, ease of drug delivery and reduce the immunosuppression inherent in these tumours.

1. https://seer.cancer.gov/statfacts/html/brain.html
2. https://www.braintumour.ca/2494/brain-tumour-facts
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234/
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2786905/
5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5084676/”
6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619015/
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735528/
8. https://www.ncbi.nlm.nih.gov/pubmed/15830341