“This triple combination therapy induced an unprecedented therapeutic response in our models,” said corresponding author Ronald DePinho, MD, professor of Cancer Biology. “The prevailing view is that pancreatic cancer is resistant to immunotherapy, but this preclinical study shows that it can be sensitive to the right combination therapy. Moreover, the presence of these targets in human pancreatic cancer samples raises the exciting possibility for such therapeutic combinations. One day can help our patients.”
Pancreatic cancer is one of the leading causes of cancer death in the United States, in part because 80% of cases are diagnosed at an advanced stage. Pancreatic cancer is also considered “non-immunogenic,” meaning it does not respond to commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This is partly due to immunosuppressive conditions in TIME, but the mechanisms behind this resistance are not fully understood.
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The researchers used high-dimensional immune profiling and single-cell RNA sequencing to study how TIME is affected by different immunotherapies. They identified specific immune checkpoint proteins, 41BB and LAG, that are highly expressed in exhausted T cells.
Researchers testing antibodies targeting these checkpoints observed that models treated with a combination of the 41BB agonist and LAG3 antagonist had slower tumor progression, higher rates of anti-tumor immunity, and significantly improved survival rates compared to treatment with the antibody alone or with other antibodies. . checkpoint inhibitors. In particular, these preclinical studies faithfully replicated human data on the lack of efficacy of anti-PD1 or anti-CTLA-4 therapy.
Pancreatic Cancer: A New Treatment
The researchers also confirmed that these two therapeutic targets were present in human pancreatic cancer samples, with 81% and 93% of patients analyzed having T cells expressing 41BB and LAG3, respectively.
Because this dual therapy combination did not completely eliminate established tumors, the researchers also explored efforts to reprogram TIME to make tumors more sensitive to immunotherapy. Initially, TIME contains many myeloid-derived suppressor cells (MDSC) that express CXCR2, a protein associated with the recruitment of immunosuppressive cells. Inhibition of CXCR2 alone reduced MDSC migration and blocked tumor growth but was not curative. This led the investigators to consider a combination targeting 41BB, LAG3, and CXCR2.
It was this triple combination that achieved complete tumor regression and improved overall survival in 90% of preclinical models. In a more stringent laboratory model that developed multiple spontaneous tumors with higher treatment resistance, the combination achieved complete tumor regression in more than 20% of cases.
“These are encouraging results, especially given the lack of effective immunotherapy options in pancreatic cancer,” DePinho said. “By targeting multiple synergistic mechanisms that inhibit the immune response, we may be able to give T cells a fighting chance to attack these tumors. Of course, we still need to see how this combination translates into a safe and effective regimen in the clinic, and we encourage other researchers to build on these results.” . We are optimistic that pancreatic cancers, and hopefully other non-immunogenic cancers, may be sensitive to combination immunotherapy.”
Source: Eurekalert
