Research on Making Cancer “Catch” the Flu Wins International Acclaim in Nature

Siddharth Balachandran, PhD, Co-Leader, Blood Cell Development and Function, and his prominent team of researchers are immersed in plumbing the mysteries of influenza viruses. So, it was an aha moment when they stumbled upon a highly inflammatory form of cell death that influenza virus triggered in infected cells.

The team wondered: “What if we could mimic an influenza infection within a tumor and trick the immune system into seeing a 'cold' tumor as 'hot' and as something to be eliminated? What if we could leverage this potent cell death to aid cancer therapy?”

Using mouse models of melanoma, the researchers tested their theory by administering the compound CBL0137. This compound induces the same form of highly inflammatory cell death that influenza virus triggers, but directly in the cancerous tissue. The resulting antiviral response put the immune system on high alert. It turned a “cold” tumor “hot” so that when paired with immunotherapy, the host immune system saw cancer as something to be destroyed.

Their virus “trick” had worked so brilliantly that the study “ADAR1 Masks the Cancer Immunotherapeutic Promise of ZBP1-Driven Necroptosis” was published in the June 16, 2022 issue of the prestigious journal Nature, with Balachandran as a lead author.

Fox Chase clinicians will begin a phase 1 proof-of-concept clinical trial in the next few months. At the helm are Fox Chase co-PI Igor Astsaturov, MD, PhD, Associate Professor, Department of Hematology/Oncology and co-PI Anthony J. Olszanski, MD, RPh, Vice Chair of Clinical Research, Department of Hematology/Oncology. The two hope to demonstrate that CBL0137 used alongside immunotherapy in patients with advanced melanoma is safe and confirms that the drug is working in humans similar to what was witnessed in the lab.

Balachandran explains, “This is an important study to determine if CBL0137 can augment immunotherapy. By combining a ‘virus mimetic’ with immunotherapy, we hope to amplify an immune response and make immunotherapy more effective for our patients.”

More good news is that the CBL0137 compound has already been tested as a single agent in patients, providing important confirmation of safety and dosing.

“That’s a big deal because typically, there’s a multi-year gap between discovering a compound and using it in patients. Here, we’re able to bypass that wait and get the compound directly into patients for use in combination with immunotherapy,” Balachandran added.