Medicosnext
Almost 80% of pancreatic cancer cases are diagnosed at an advanced stage, and this deadly cancer is also considered to be “non-immunogenic,” that is, it is unresponsive to commonly used immune checkpoint inhibitors due partly to the immunosuppressive conditions in the tumor immune microenvironment (TIME). Now, a new immunotherapy combination that targets checkpoints in both T cells and myeloid suppressor cells and reprograms the TIME, significantly improving anti-tumor responses in preclinical models of pancreatic cancer, has been discovered by researchers at the University of Texas MD Anderson Cancer Center. They found that neutralizing several immunosuppressive mechanisms of the TIME noticeably improved survival rates in laboratory models.
According to Ronald DePinho, M.D., professor of Cancer Biology, while currently it is believed that pancreatic cancer is impervious to immunotherapy, this study has shown that the right combination therapy can make it susceptible to treatment. The researchers found that models treated with a combination of 41BB agonist and LAG3 antagonists had slower tumor progression, higher levels of anti-tumor immunity indicators, and significantly improved survival rates, compared to treatment with either antibody alone or with other checkpoint inhibitors. It was also confirmed these two therapeutic targets are present in human pancreatic cancer samples.
While examining efforts to reprogram the TIME to further sensitize tumors to immunotherapy, the researchers discovered that, at baseline, the TIME contained good quantities of myeloid-derived suppressor cells (MDSCs) expressing CXCR2 (a protein associated with recruiting immunosuppressive cells). They then decided to consider a combination targeting 41BB, LAG3, and CXCR2, which resulted in complete tumor regression and improved overall survival in 90% of preclinical models. Further studies need to be done as to how this combination will translate into a safe and effective regimen in a clinical setting.
