Pancreatic cancer, notorious for its aggressive nature and poor survival rates, may have a new therapeutic avenue. Researchers at MIT have developed a triple-drug immunotherapy that completely eliminated pancreatic tumors in 25% of mice and shrank tumors in approximately half the treated animals. This innovative approach, combining PD-1 and TIGIT inhibitors with a CD40 agonist antibody, is slated for clinical trials later this year.
Overcoming Immunosuppression in Pancreatic Cancer
Pancreatic cancer affects approximately 60,000 Americans annually and is characterized by a dismal five-year survival rate of less than 10%. Immunotherapy, which has revolutionized the treatment of other cancers, has shown limited success in pancreatic cancer due to the tumor's immunosuppressive environment. While checkpoint inhibitors targeting the PD-1/PD-L1 axis have proven effective in melanoma and lung cancer, they have had minimal impact on pancreatic tumors.
The MIT team, led by William Freed-Pastor and Tyler Jacks, discovered that pancreatic tumors express high levels of CD155, a protein that activates the TIGIT receptor on T cells, leading to T cell exhaustion. This mechanism is similar to the PD-1/PD-L1 axis, where T cell activity is suppressed. "The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells," Freed-Pastor explained.
Synergistic Drug Combination
To overcome this immunosuppression, the researchers tested a combination of drugs targeting both the PD-1/PD-L1 and CD155/TIGIT pathways, along with a CD40 agonist antibody. CD40 agonists activate T cells and promote their infiltration into tumors. In mouse models, the combination of a CD40 agonist antibody with either a PD-1 inhibitor or a TIGIT inhibitor only halted tumor growth in some animals. However, the triple combination of CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor resulted in significant tumor shrinkage, with complete eradication in 25% of the mice.
Clinical Trial and Future Directions
Based on these promising results, a clinical trial evaluating the triple combination is expected to commence later this year. The MIT team collaborated with the Lustgarten Foundation for Pancreatic Cancer Research and two pharmaceutical companies to secure access to a PD-1 inhibitor, a TIGIT inhibitor, and a CD40 agonist antibody, all of which have reached phase 2 clinical trials individually. "This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease," Jacks said.
In addition to the clinical trial, the researchers plan to identify which types of pancreatic tumors are most likely to respond to this treatment. They are also conducting further animal studies to enhance the treatment's effectiveness beyond the 50% response rate observed in the initial study.
