Study identifies potential RAS inhibitor-immunotherapy strategy for pancreatic cancer

Pancreatic cancer often resists immunotherapies, but researchers have identified a potential strategy combining RAS inhibitors with a novel immunotherapy agent. In pancreatic tumors with RAS mutations, RAS inhibitors cause massive cell death and reduce immunosuppression. A new study published in the journal Cell suggests that pairing a RAS inhibitor with an agent called 21h10, an AI-designed mimic of the immune-related cytokine interleukin (IL)-21, could produce a durable response.

21h10, developed by David Baker's lab at the University of Washington, improves the drug-like qualities and stability of naturally occurring IL-21. In mouse models of pancreatic cancer, this combination initially triggered an immune response that turned the temporary effects of RAS inhibition into a long-lasting effect. The researchers found that 21h10 primes and activates CD4 T cells in the cancer, leading them to produce a signal called interferon-γ (IFN-γ). This IFN-γ prompts innate immune cells called macrophages to destroy tumor cells.

Previous studies with 21h10 in melanoma and colorectal cancer models showed efficacy with CD8 T cells against the tumors. However, in pancreatic cancer, CD4 T cells appear to be more effective. The study indicates that durable remissions for pancreatic cancer patients might be achievable using this novel combination of immunotherapy and RAS-targeted therapy.

While CD4 T cells from pancreatic cancer patients produced IFN-γ in response to 21h10, more research is required to fully understand the approach's efficacy and safety.