The pancreatic cancer It is a leading cause of cancer death because it is usually diagnosed when it is already in an advanced stage. Additionally, this type of cancer is considered “non-immunogenic,” meaning it does not respond to commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This failure to respond to immunotherapy it is due in part to immunosuppressive conditions in the tumor immune microenvironment (TME), but the mechanisms by which this resistance occurs are not well understood.
A new discovery, however, could help improve the treatment of pancreatic cancersince a group of scientists from the MD Anderson Cancer Center of the University of Texas discovered a new combination of immunotherapy target checkpoints in both T cells and myeloid suppressor cells, which successfully reprogrammed the tumor immune microenvironment and significantly improved antitumor responses in preclinical models of pancreatic cancer.
Researchers used comprehensive immunological profiles in human and mouse pancreatic tumors to identify mechanisms of resistance to immunotherapy and investigate potential therapeutic targets. They found that neutralizing several immunosuppressive mechanisms of TME significantly improved survival rates in laboratory models, suggesting a potential treatment option for this deadly and hard-to-fight cancer. Their results have been published in Cancer of nature.
“The prevailing view has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows it may be vulnerable to appropriate combination therapy.”
“This triple combination therapy resulted in an unprecedented curative response in our models,” said Dr. Ronald DePinho, professor of cancer biology and author of the paper. “The prevailing view has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows it may be vulnerable to appropriate combination therapy. Furthermore, the presence of these targets in human pancreatic cancer samples raises the exciting possibility that such therapeutic combinations could one day help our patients.”
Combination immunotherapy for the treatment of various types of cancer
Researchers used high-dimension immunoprofiling and single-cell RNA sequencing to study how a variety of immunotherapies affected the tumor immune microenvironment. They identified specific immune checkpoint proteins, 41BB and LAG, which were highly expressed in the depleted T cells.
when they tried antibodies directed at these checkpoints found that models treated with a 41BB agonist and a LAG3 antagonist had slower tumor progression and had higher levels of antitumor immunity markers and significantly better survival rates than treatment with antibodies alone or with other control point inhibitors . These preclinical studies, in particular, closely mirrored the human data in their lack of efficacy of anti-PD1 or anti-CTLA-4 therapy.
The researchers also confirmed that these two therapeutic targets are present in human pancreatic cancer samples, with 81% and 93% of patients tested with T cells expressing 41BB and LAG3, respectively. However, this dual therapy did not completely eliminate the tumors, so these scientists continued to look into TME and decided to try a combination targeting 41BB, LAG3 and CXCR2 (a protein associated with immunosuppressive cell recruitment).
With this triple combination they achieved complete regression of the tumor and improve overall survival in 90% of preclinical models. In a more accurate laboratory model that develops many spontaneous tumors that are more resistant to treatment, the combination achieved complete tumor regression in more than 20 percent of cases.
“These are encouraging results, especially considering the lack of effective immunotherapy options in pancreatic cancer,” DePinho said. “By targeting multiple synergistic mechanisms that hamper the immune response, we can give T cells a fighting chance to attack these tumors. Of course, we have yet to see how this combination translates into a safe and effective clinical regimen,” and we invite other investigators to build on these findings. We are optimistic that pancreatic cancers, and hopefully other non-immunogenic cancers, could eventually they become vulnerable to combination immunotherapy”.
