Research Spotlight: Improving the Efficacy of Immune Checkpoint Blockers in Pancreatic Cancer

Rakesh Jain, PhD, director of the Edwin Steele Laboratories for Tumor Biology in the Department of Radiation Oncology at Massachusetts General Hospital and Andrew Werk Professor of Radiation Oncology at Harvard Medical School, is senior and corresponding author of a paper published in the Journal for ImmunoTherapy of Cancer, “IL-1β Blockade Prevents Cardiotoxicity and Improves Efficacy of Immune Checkpoint Blockers and Chemotherapy against Pancreatic Cancer in Mice with Obesity.”

Q: How would you summarize your study for a lay audience?

Immune checkpoint blockers (ICBs) have revolutionized cancer therapy, yet they remain largely ineffective in treating pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. ICBs can cause severe immune-related adverse events (irAEs), including fatal cardiac toxicity known as myocarditis, but their causes are unclear.

Obesity is a risk factor in PDAC that may modulate ICB efficacy. Here, we found that following chemo and ICB therapy, obese mice with pancreatic cancer exhibited myocarditis and had an elevated serum IL-1β levels.

Q: What question were you investigating?

What are the mechanisms behind the failure of immune checkpoint therapy (ICB) in patients with PDAC, the most common form of pancreatic cancer, and how does obesity affect the risk of immune-related adverse events (irAEs)?

Q: What methods or approach did you use?

We employed a clinically relevant mouse model of pancreatic ductal adenocarcinoma (PDAC) and irAEs that incorporated three key features of the human disease: 

(1) High-fat diet-induced obesity
(2) Tumor growing in the pancreas
(3) A therapeutic regimen combining the standard of care chemotherapy (FOLFIRINOX) with dual ICB (anti-PD-1 and anti-CTLA-4 antibodies).

Our model recapitulated key irAEs associated with ICB therapy in the context of obesity, without relying on genetic deletion of checkpoint molecules, or subcutaneous tumor implantation—approaches commonly used in previous studies that may introduce confounding factors.

Q: What did you find?

Following chemoimmunotherapy, obese mice exhibited myocarditis associated with elevated serum IL-1β levels.

Blocking IL-1β prevented myocarditis, reduced cardiac fibrosis, and enhanced the anti-tumor efficacy of combined chemotherapy and dual ICBs, which led to a significant improvement in overall survival in PDAC-bearing obese mice.

Q: What are the implications?

Our study provides compelling data and the rationale to test an FDA-approved anti-IL-1 antibody in combination with chemotherapy and dual ICB in PDAC patients with obesity.

Q: What are the next steps?

ICB has failed to induce benefits in PDAC patients, and obesity may promote ICB resistance. 

The next step is to start a clinical trial of an anti-IL-1β agent with FOLFIRINOX and anti-PD-1 and anti-CTLA-4 dual ICB therapy for PDAC patients with obesity.