Dr. Michael Castro and colleagues have joined with the Musella Foundation to raise funds for a proof of concept trial aimed at establishing immunotherapy for the treatment of glioblastoma.

The Challenge

Inducing permanent antitumor immunity is the holy grail of modern oncology. For many malignancies, immunotherapy has become the 4th pillar of disease management (surgery, radiation, chemotherapy, and immunotherapy). But glioblastoma (GBM) is not yet on the list.

Loss of APM and CMV

Investigators recently identified that as many as 80% of GBM patients lack the antigen presenting machinery (APM) coded by MHC1 genes on the surface of the tumor cell that is essential for the tumor to show its mutations to the immune system. In effect, loss of APM permits the cancer to fly under the radar. At the same time, cytomegalovirus (CMV), is identified in nearly all GBM tumors, but the immune system fails to eradicate the infection or the cancer cell hosting it. Like other oncogenic viruses such as HPV, CMV is able to takedown APM in order to allow virally infected cells to evade the immune response.

Preliminary data from Sweden suggest that GBM patients taking the CMV antibiotic, valganciclovir (Valcyte®) survive longer. While these findings have been criticized since they require that patients must stay on the drug to get a benefit (and therefore commits the bias of only selecting the "good" responders), the finding makes mechanistic sense considering that cells would first need to complete one or more cell divisions in order to suppress CMV replication and protein production in the presence of Valcyte. Long duration on treatment may be a necessity even as it introduces procedural challenges to studying the question.

What if Valcyte can rescue APM?

While the idea that blocking CMV would make immunotherapy feasible for GBM patients is deceptively simple, the dots have never been connected. A reasonable hypothesis is that the suppression of CMV proteins involved in blocking the transit of MHC1 proteins to the cell surface will re-establish one of the most essential elements of an anti-tumor immune response, namely that the immune system must have the tumor antigens "presented" by APM at the cell surface.

Methodology

Dr. Castro proposes a "proof of concept" trial to grow GBM in cell culture and assess whether an absent APM can be coaxed to reappear by treating the cells with Valcyte. The goal is to raise at least $100,000 to study glioblastoma from patients in cell culture to demonstrate recovery of APM and prove the mechanism of action. The study will look elaborately at the genomic and transcriptomic factors that govern APM. To fulfill the criteria for proof.

Implications

A successful study would serve as a foundation for using PD-1/L1 checkpoint immunotherapy in conjunction with Valcyte to rescue antigen presentation. This approach makes use of medicines that are readily at hand in a novel combination. No new drugs would need approval to realize the benefit of this approach in the foreseeable future.

About the Investigator

The study is being led by Dr. Michael P. Castro, a proponent of molecular diagnosis to overcome mechanisms of resistance to immunotherapy and other anti-cancer strategies. He is board-certified in medical oncology and neuro-oncology and manages patients with glioblastoma and other malignancies. He also serves as Chief Medical Officer for Cellworks, a computational biology modeling company that provides engineering-level insight into drug response, drug resistance, and the malignant phenotype.

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